rs144537241

Positions:

chr12-21852488-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_020297.4(ABCC9):c.2523C>T(p.Ala841=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,611,438 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 28 hom. )

Consequence

ABCC9
NM_020297.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: -0.530

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 12-21852488-G-A is Benign according to our data. Variant chr12-21852488-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35628.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Likely_benign=1, Uncertain_significance=1}. Variant chr12-21852488-G-A is described in Lovd as [Benign]. Variant chr12-21852488-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.53 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00341 (519/152162) while in subpopulation NFE AF= 0.00575 (391/68006). AF 95% confidence interval is 0.00528. There are 2 homozygotes in gnomad4. There are 229 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4 linkuse as main transcript	c.2523C>T	p.Ala841=	synonymous_variant	23/40	ENST00000261200.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC9	ENST00000261200.9 linkuse as main transcript	c.2523C>T	p.Ala841=	synonymous_variant	23/40	5	NM_020297.4	P4	O60706-2
	ENST00000539874.1 linkuse as main transcript	n.332-17094G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00341

AC:

519

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00575

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00326

AC:

812

AN:

249336

Hom.:

AF XY:

0.00353

AC XY:

476

AN XY:

134920

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00235

Gnomad FIN exome

AF:

0.00126

Gnomad NFE exome

AF:

0.00547

Gnomad OTH exome

AF:

0.00279

GnomAD4 exome

AF:

0.00491

AC:

7167

AN:

1459276

Hom.:

Cov.:

AF XY:

0.00480

AC XY:

3484

AN XY:

726026

show subpopulations

Gnomad4 AFR exome

AF:

0.000837

Gnomad4 AMR exome

AF:

0.000962

Gnomad4 ASJ exome

AF:

0.00268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00190

Gnomad4 FIN exome

AF:

0.00171

Gnomad4 NFE exome

AF:

0.00581

Gnomad4 OTH exome

AF:

0.00477

GnomAD4 genome

AF:

0.00341

AC:

519

AN:

152162

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

229

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00152

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00575

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00457

Hom.:

Bravo

AF:

0.00335

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00600

EpiControl

AF:

0.00622

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 10, 2012	Ala841Ala in Exon 21 of ABCC9: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 0.6% (43/7020) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs144537241). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ABCC9: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

Dilated cardiomyopathy 1O

Uncertain:1Benign:1

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hypertrichotic osteochondrodysplasia Cantu type

Benign:1

Benign, 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 02, 2017

- -

Primary dilated cardiomyopathy

Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 04, 2015

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

9.0

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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