rs61688134

Positions:

• chr12-21864476-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 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. 14/24 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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ABCC9. . Gene score misZ 4.9694 (greater than the threshold 3.09). Trascript score misZ 7.023 (greater than threshold 3.09). GenCC has associacion of gene with hypertrichotic osteochondrodysplasia Cantu type, dilated cardiomyopathy, acromegaloid facial appearance syndrome, Brugada syndrome, atrial fibrillation, familial, 12, intellectual disability and myopathy syndrome, dilated cardiomyopathy 1O, familial isolated dilated cardiomyopathy, hypertrichosis-acromegaloid facial appearance syndrome.
• 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 id is 35627.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=10, Uncertain_significance=1}. Variant chr12-21864476-C-T is described in Lovd as [Benign]. Variant chr12-21864476-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9	c.2200G>A	p.Val734Ile	missense_variant, splice_region_variant	19/40	5	NM_020297.4	ENSP00000261200	P4
	ENST00000539874.1	n.332-5106C>T		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.00736 AC: 1844 AN: 250682 Hom.: 9 AF XY: 0.00730 AC XY: 989 AN XY: 135526

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 SAS exome AF: 0.0000654

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

Gnomad4 AFR exome AF: 0.00225

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.00355

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00320

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.00985

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

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.00909

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0102 Hom.: 10

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 17, 2012	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2021	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. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ABCC9: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

Dilated cardiomyopathy 1O Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 02, 2017

- -

Ventricular tachycardia;C0878544:Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 28, 2019

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2015

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. -

Myocardial infarction Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

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
MutationTaster	Benign	0.99	D;D;D
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

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

Publications

LitVar

Other links and lift over

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