12-21807443-A-G

Position:

• chr12-21807443-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP3

The NM_020297.4(ABCC9):​c.4352T>C​(p.Val1451Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ABCC9 NM_020297.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.07

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC9	NM_020297.4	c.4352T>C	p.Val1451Ala	missense_variant	38/40	ENST00000261200.9	NP_064693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9	c.4352T>C	p.Val1451Ala	missense_variant	38/40	5	NM_020297.4	ENSP00000261200.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251254 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461670 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1O Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

ClinVar contains an entry for this variant (Variation ID: 45414). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). This variant is present in population databases (rs397517190, gnomAD 0.006%). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1451 of the ABCC9 protein (p.Val1451Ala). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 02, 2012

The Val1451Ala variant (ABCC9) has not been reported in the literature nor previ ously identified by our laboratory. Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, and SIFT) suggest that the variant may i mpact the protein but PolyPhen-2 predicts it to be benign. However, though this information is not predictive enough to determine pathogenicity. In summary, add itional information is needed to fully assess the clinical significance of the V al1451Ala variant. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jun 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	0.21	N;.;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.1	N;N;N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.015	D;D;D
Sift4G	Uncertain	0.042	D;T;D
Polyphen		0.91	P;.;B
Vest4		0.48
MutPred		0.69		Gain of disorder (P = 0.0547);.;Gain of disorder (P = 0.0547);
MVP		0.92
MPC		0.85
ClinPred		0.75	D
GERP RS		5.0
Varity_R		0.33
gMVP		0.96

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

Other links and lift over

dbSNP: rs397517190; hg19: chr12-21960377;