rs141281214

Positions:

• chr12-21863055-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BS1 BS2

The NM_020297.4(ABCC9):​c.2238-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000759 in 1,588,992 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00076 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (8 hom.)
• Consequence: ABCC9 NM_020297.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:11
• Conservation: PhyloP100: 5.91

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]

ENSG00000257022 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02172043 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 3, new splice context is: tctttttcatttttcaatAGgaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 12-21863055-C-T is Benign according to our data. Variant chr12-21863055-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162688.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, Benign=4}. Variant chr12-21863055-C-T is described in Lovd as [Benign]. Variant chr12-21863055-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000759 (108/142264) while in subpopulation SAS AF= 0.00548 (24/4382). AF 95% confidence interval is 0.00378. There are 1 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC9	NM_020297.4	c.2238-1G>A		splice_acceptor_variant, intron_variant		ENST00000261200.9	NP_064693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9	c.2238-1G>A		splice_acceptor_variant, intron_variant		5	NM_020297.4	ENSP00000261200.4

Frequencies

GnomAD3 genomes AF: 0.000760 AC: 108 AN: 142160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000792

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000221

Gnomad ASJ AF: 0.0151

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00547

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00333

Gnomad NFE AF: 0.000366

Gnomad OTH AF: 0.00156

GnomAD3 exomes AF: 0.00147 AC: 358 AN: 243104 Hom.: 2 AF XY: 0.00167 AC XY: 221 AN XY: 132124

Gnomad AFR exome AF: 0.0000653

Gnomad AMR exome AF: 0.0000603

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00639

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.000759 AC: 1098 AN: 1446728 Hom.: 8 Cov.: 28 AF XY: 0.000899 AC XY: 648 AN XY: 720666

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00546

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000198

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.000759 AC: 108 AN: 142264 Hom.: 1 Cov.: 32 AF XY: 0.000811 AC XY: 56 AN XY: 69026

Gnomad4 AFR AF: 0.0000789

Gnomad4 AMR AF: 0.000221

Gnomad4 ASJ AF: 0.0151

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00548

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000366

Gnomad4 OTH AF: 0.00155

Alfa AF: 0.00104 Hom.: 4

Bravo AF: 0.000608

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00158 AC: 192

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	This variant is associated with the following publications: (PMID: 26656175, 28166811, 23861362, 29030401, 28881617, 26046366, 30847666) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ABCC9: BS2 -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 06, 2015	Variant classified as Uncertain Significance - Favor Benign. The c.2238-1G>A var iant in ABCC9 has been identified by our laboratory in two individuals with DCM, one of whom carried a second pathogenic variant in another gene. It has also be en identified in 0.7% (118/16384) of South Asian chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs141281214). This frequency raises doubt as to whether this variant can cause a dominant disease. However, this variant is expected to abolish the 3? splice site of exon 18 and create a novel spice site 3 bases further downstream, which would result in an i n-frame deletion of one amino acid. In summary, additional information is needed to fully assess the clinical significance of the c.2238-1G>A variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2020	Variant summary: ABCC9 c.2238-1G>A is located in a canonical splice-site, which are typically predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. In the case of this variant, however, 4/4 computational tools predict that the variant abolishes a 3' acceptor site, but strengthens or creates a cryptic 3' acceptor site three bases downstream, which would be predicted to result in the deletion of only one amino acid from the protein. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 243104 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 59- fold the estimated maximal expected allele frequency for a pathogenic variant in ABCC9 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.2238-1G>A has been reported in the literature in individuals affected with Cardiomyopathy (examples- Bottillo_2016, Cirino_2017, Seidelmann_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They cited the variant as benign (n=1), likley benign (n=2), and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

ABCC9-related disorder Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 18, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 24, 2023	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Dilated cardiomyopathy 1O Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Hypertrichotic osteochondrodysplasia Cantu type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 18, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2018

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
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.97	D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: -4
DS_AL_spliceai		0.79		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: rs141281214; hg19: chr12-22015989;