rs61688134

Variant names:

• chr12-21864476-C-T
• rs61688134
• NM_020297.4:c.2200G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020297.4(ABCC9):​c.2200G>A​(p.Val734Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,587,612 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0074 (4 hom., cov: 32)
  • Exomes 𝑓: 0.011 (93 hom.)
• Consequence: ABCC9 NM_020297.4 missense, splice_region
• Scores: Splicing: ADA: 0.03439
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16
• Conservation: PhyloP100: 2.92
• Publications: 29 publications found

Genes affected

ABCC9 (HGNC:60): (ATP binding cassette subfamily C member 9) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein is thought to form ATP-sensitive potassium channels in cardiac, skeletal, and vascular and non-vascular smooth muscle. Protein structure suggests a role as the drug-binding channel-modulating subunit of the extra-pancreatic ATP-sensitive potassium channels. Mutations in this gene are associated with cardiomyopathy dilated type 1O. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2011]

ABCC9 Gene-Disease associations (from GenCC):

• hypertrichotic osteochondrodysplasia Cantu type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dilated cardiomyopathy 1O

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intellectual disability and myopathy syndrome

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• acromegaloid facial appearance syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrichosis-acromegaloid facial appearance syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation, familial, 12

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000257022 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008691698).
• BP6: Variant 12-21864476-C-T is Benign according to our data. Variant chr12-21864476-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35627.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00736 (1120/152264) while in subpopulation NFE AF = 0.0118 (803/68010). AF 95% confidence interval is 0.0111. There are 4 homozygotes in GnomAd4. There are 506 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 Unknown,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC9	NM_020297.4	c.2200G>A	p.Val734Ile	missense_variant, splice_region_variant	Exon 19 of 40	ENST00000261200.9	NP_064693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9	c.2200G>A	p.Val734Ile	missense_variant, splice_region_variant	Exon 19 of 40	5	NM_020297.4	ENSP00000261200.4

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 1120 AN: 152146 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00911

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00736 AC: 1844 AN: 250682 AF XY: 0.00730

Gnomad AFR exome AF: 0.00235

Gnomad AMR exome AF: 0.00993

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00787

GnomAD4 exome AF: 0.0107 AC: 15378 AN: 1435348 Hom.: 93 Cov.: 27 AF XY: 0.0104 AC XY: 7422 AN XY: 715544

African (AFR) AF: 0.00225 AC: 74 AN: 32898

American (AMR) AF: 0.0102 AC: 456 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00355 AC: 92 AN: 25950

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39494

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85760

European-Finnish (FIN) AF: 0.00320 AC: 171 AN: 53380

Middle Eastern (MID) AF: 0.00280 AC: 16 AN: 5714

European-Non Finnish (NFE) AF: 0.0128 AC: 13979 AN: 1088070

Other (OTH) AF: 0.00985 AC: 586 AN: 59476

GnomAD4 genome AF: 0.00736 AC: 1120 AN: 152264 Hom.: 4 Cov.: 32 AF XY: 0.00680 AC XY: 506 AN XY: 74458

African (AFR) AF: 0.00253 AC: 105 AN: 41558

American (AMR) AF: 0.00909 AC: 139 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0118 AC: 803 AN: 68010

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00983 Hom.: 13

Bravo AF: 0.00812

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0132 AC: 113

ExAC AF: 0.00698 AC: 847

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:8

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 07, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 30, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCC9 c.2200G>A (p.Val734Ile) results in a conservative amino acid change located in the ABC transporter-like (IPR003439) and AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This variant is also located in an exonic splice region altering the second nucleotide of exon 17. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0073 in 253636 control chromosomes, predominantly at a frequency of 0.012 within the Non-Finnish European subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 480 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC9 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2200G>A has been reported in the literature in individuals affected with cardiomyopathy, myocardial infarction, arrhythmia (example, Zimmerman 2010, Bottillo 2016, Minoretti 2006, Hu 2013, Celestino-Soper 2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been observed in patients undergoing panel testing for HCM (hypertrophic cardiomyopathy) at our laboratory and in the literature (example, MYBPC3 c.1484G>A, p.Arg495Gln, our laboratory; MYBPC3 c.2309-2A>G, Bottillo_2016) and SCN5A 3891insA in a proband with sinus bradycardia, AV block, ventricular bigeminy and a global ER pattern (Hu_2013), providing supporting evidence for a benign role. At least two publications reporting experimental evidence evaluating an impact on protein function were ascertained in the context of this evaluation. These reported that the variant, p.Val734Ile, may affect the function of ABCC9 potassium ATP channel complex. However the in-vivo physiological consequences of these findings are not cleary established (Smith_2013, Hu_2013). In a case-control study that included 584 Precocious Myocardial Infarction (PMI) patients and 873 controls, the frequency of 734Ile carriers was significantly higher in MI patients as compared to controls (crude OR=5.52, 95% CI=1.53-19.84, P=0.0075) (Minoretti 2006). However, larger cohort studies are needed to confirm whether this variant is associated with Precocious Myocardial Infarction. Therefore, these studies does not allow convincing conclusions about the variant effect. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=4; likely benign, n=1; VUS, n=1). Based on the evidence outlined above and the predominant consensus among peers supporting a non-actionable outcome in an inherited germline setting, the variant was classified as benign. -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 17, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Val734Ile in exon 17 of ABCC9: This variant is not expected to be clinically sig nificant because it has been identified in 1.2% (87/7012) of European American c hromosomes chromosomes from a broad population by the NHLBI Exome Sequencing Pro ject (http://evs.gs.washington.edu/EVS; dbSNP rs61688134). Minoretti and colleag ues (2006) reported a possible association with an increased risk for myocardial infarction (based on an increased frequency in cases compared to controls), tho ugh this variant is unlikely to be disease causing when present in isolation. -

not provided Benign:3

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCC9: BS1, BS2 -

Dilated cardiomyopathy 1O Uncertain:1 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy Benign:1

Nov 02, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ventricular tachycardia;C0878544:Cardiomyopathy Benign:1

May 28, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myocardial infarction Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiovascular phenotype Benign:1

Sep 24, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	.;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.42	T;T;T
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.78	N;.;N
PhyloP100		2.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.10	N;N;N
REVEL	Benign	0.29
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0040	B;.;B
Vest4		0.25
MVP		0.83
MPC		0.54
ClinPred		0.014	T
GERP RS		5.0
Varity_R		0.093
gMVP		0.25
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.034
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61688134; hg19: chr12-22017410; COSMIC: COSV99038964;