chr12-21875696-C-T
Variant summary
Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_020297.4(ABCC9):c.2050G>A(p.Gly684Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000727 in 1,612,698 control chromosomes in the GnomAD database, including 5 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
Consequence
NM_020297.4 missense
Scores
Clinical Significance
Conservation
Publications
- hypertrichotic osteochondrodysplasia Cantu typeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- dilated cardiomyopathy 1OInheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- intellectual disability and myopathy syndromeInheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- acromegaloid facial appearance syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hypertrichosis-acromegaloid facial appearance syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Brugada syndromeInheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- atrial fibrillation, familial, 12Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Benign. The variant received -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000467 AC: 71AN: 152132Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000837 AC: 210AN: 250964 AF XY: 0.000950 show subpopulations
GnomAD4 exome AF: 0.000755 AC: 1102AN: 1460448Hom.: 5 Cov.: 29 AF XY: 0.000859 AC XY: 624AN XY: 726674 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000466 AC: 71AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32AN XY: 74446 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Benign:6
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ABCC9: BS2 -
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not specified Benign:4
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Variant summary: ABCC9 c.2050G>A (p.Gly684Ser) results in a non-conservative amino acid change located in the ABC transporter-like of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 250964 control chromosomes. The observed variant frequency is approximately 33.47 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC9 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.2050G>A has been reported in the literature in individuals affected with DCM (Pugh_2014). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
p.Gly684Ser in exon 15 of ABCC9: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (57/16406) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs148174226). -
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Dilated cardiomyopathy 1O Uncertain:1Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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Hypertrichotic osteochondrodysplasia Cantu type Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Cardiomyopathy Benign:1
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Arrhythmogenic right ventricular cardiomyopathy Benign:1
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ABCC9-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiovascular phenotype Benign:1
This alteration is classified as likely 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at