rs1220942080

Positions:

chr12-21882774-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_020297.4(ABCC9):c.2011G>A(p.Ala671Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000311 in 1,608,920 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: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ABCC9
NM_020297.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.47

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC9	NM_020297.4 linkuse as main transcript	c.2011G>A	p.Ala671Thr	missense_variant	16/40	ENST00000261200.9	NP_064693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9 linkuse as main transcript	c.2011G>A	p.Ala671Thr	missense_variant	16/40	5	NM_020297.4	ENSP00000261200	P4	O60706-2
	ENST00000539874.1 linkuse as main transcript	n.413-5074C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152090

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456830

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725140

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:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1O

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 671 of the ABCC9 protein (p.Ala671Thr). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 533283). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC9 protein function. 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 provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 21, 2022

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The p.A671T variant (also known as c.2011G>A), located in coding exon 14 of the ABCC9 gene, results from a G to A substitution at nucleotide position 2011. The alanine at codon 671 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

2.0

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.64

Sift

Benign

0.031

D;D

Sift4G

Uncertain

0.020

D;D

Polyphen

1.0

D;D

Vest4

0.83

MutPred

0.39

Gain of phosphorylation at A671 (P = 0.0517);Gain of phosphorylation at A671 (P = 0.0517);

MVP

0.87

MPC

1.5

ClinPred

0.98

GERP RS

4.5

Varity_R

0.12

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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