chr12-21852488-G-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_020297.4(ABCC9):​c.2523C>T​(p.Ala841Ala) 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

2

Clinical Significance

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

Conservation

PhyloP100: -0.530

Publications

4 publications found
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 Gene-Disease associations (from GenCC):
  • hypertrichotic osteochondrodysplasia Cantu type
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • dilated cardiomyopathy 1O
    Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • intellectual disability and myopathy syndrome
    Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • acromegaloid facial appearance syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hypertrichosis-acromegaloid facial appearance syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Brugada syndrome
    Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
  • dilated cardiomyopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • atrial fibrillation, familial, 12
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 2 Unknown,AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCC9NM_020297.4 linkc.2523C>T p.Ala841Ala synonymous_variant Exon 23 of 40 ENST00000261200.9 NP_064693.2 O60706-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCC9ENST00000261200.9 linkc.2523C>T p.Ala841Ala synonymous_variant Exon 23 of 40 5 NM_020297.4 ENSP00000261200.4 O60706-2

Frequencies

GnomAD3 genomes
AF:
0.00341
AC:
519
AN:
152044
Hom.:
2
Cov.:
32
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
GnomAD2 exomes
AF:
0.00326
AC:
812
AN:
249336
AF XY:
0.00353
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 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.:
28
Cov.:
34
AF XY:
0.00480
AC XY:
3484
AN XY:
726026
show subpopulations
African (AFR)
AF:
0.000837
AC:
28
AN:
33470
American (AMR)
AF:
0.000962
AC:
43
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00268
AC:
70
AN:
26124
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39668
South Asian (SAS)
AF:
0.00190
AC:
164
AN:
86256
European-Finnish (FIN)
AF:
0.00171
AC:
87
AN:
50996
Middle Eastern (MID)
AF:
0.00434
AC:
25
AN:
5766
European-Non Finnish (NFE)
AF:
0.00581
AC:
6462
AN:
1111904
Other (OTH)
AF:
0.00477
AC:
288
AN:
60374
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.457
Heterozygous variant carriers
0
366
731
1097
1462
1828
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
252
504
756
1008
1260
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00341
AC:
519
AN:
152162
Hom.:
2
Cov.:
32
AF XY:
0.00308
AC XY:
229
AN XY:
74372
show subpopulations
African (AFR)
AF:
0.00152
AC:
63
AN:
41504
American (AMR)
AF:
0.00118
AC:
18
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00317
AC:
11
AN:
3472
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5184
South Asian (SAS)
AF:
0.00249
AC:
12
AN:
4818
European-Finnish (FIN)
AF:
0.00104
AC:
11
AN:
10584
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.00575
AC:
391
AN:
68006
Other (OTH)
AF:
0.00426
AC:
9
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
31
61
92
122
153
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00466
Hom.:
1
Bravo
AF:
0.00335
Asia WGS
AF:
0.000577
AC:
2
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
Apr 19, 2014
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

May 10, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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). -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not provided Benign:3
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

May 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ABCC9: BP4, BP7, BS2 -

Nov 09, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dilated cardiomyopathy 1O Uncertain:1Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Jan 31, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hypertrichotic osteochondrodysplasia Cantu type Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Nov 02, 2017
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Primary dilated cardiomyopathy Benign:1
Jun 04, 2015
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Cardiovascular phenotype Benign:1
Jun 19, 2015
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
PhyloP100
-0.53
Mutation Taster
=92/8
polymorphism

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

Other links and lift over

dbSNP: rs144537241; hg19: chr12-22005422; API