rs533032970

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_020297.4(ABCC9):c.2746C>T(p.Arg916Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ABCC9
NM_020297.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.96

Variant links:

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 links:

ENSG00000257022 (HGNC:):

ENSG00000257022 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the ABCC9 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 4.9694 (above the threshold of 3.09). Trascript score misZ: 7.023 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC9	NM_020297.4 link	c.2746C>T	p.Arg916Trp	missense_variant	Exon 24 of 40	ENST00000261200.9	NP_064693.2	O60706-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9 link	c.2746C>T	p.Arg916Trp	missense_variant	Exon 24 of 40	5	NM_020297.4	ENSP00000261200.4		O60706-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250706

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135518

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461424

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 16, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

SCICD Classification: variant of uncertain significance based on limited data to associate this gene with disease and lack of case data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: ABCC9: The ABCC9 gene encodes a cassette-binding protein that interacts with the Kir6.2 potassium channel. It is a gene of uncertain significance as its association with cardiomyopathy and atrial fibrillation is only emerging. ABCC9 is tolerant of both missense and loss of function variation, per a comparison or cases vs. patients with cardiomyopathy (Walsh et al 2016) and ExAC. Case data (not including our patient): ClinVar: not present. Cases in the literature: none reported. Segregation data: none reported. Functional data: none reported. In silico data (missense variants only): Per the test report, "Computational prediction tools and conservation analysis suggest that the p.Arg916Trp variant may impact the protein, though this information is not predictive enough to determine pathogenicity." Conservation data: The arginine at codon 916 is completely conserved across species. Neighboring amino acids are also conserved. Nearby pathogenic variants at this codon or neighboring codons: none. Population data: Highest MAF in South Asian population: 0.003%. The variant was reported online in 2 of 122,758 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 15,385 individuals of South Asian descent (MAF=0.003%) and 1 of 55,592 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

Sep 22, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -

not specified

Uncertain:1

Jun 28, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg916Trp variant in ABCC9 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction to ols and conservation analysis suggest that the p.Arg916Trp variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the p.Arg916Trp variant is unce rtain -

Dilated cardiomyopathy 1O

Uncertain:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 916 of the ABCC9 protein (p.Arg916Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ABCC9-related conditions. ClinVar contains an entry for this variant (Variation ID: 517469). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCC9 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

.;.;D

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Uncertain

2.2

M;.;M

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.52

MutPred

0.40

Loss of disorder (P = 0.0127);.;Loss of disorder (P = 0.0127);

MVP

0.93

MPC

1.7

ClinPred

0.98

GERP RS

3.6

Varity_R

0.34

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over