chr11-47349782-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2
The NM_000256.3(MYBPC3):c.646G>A(p.Ala216Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,605,254 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A216A) has been classified as Likely benign.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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MYBPC3 | ENST00000545968.6 | c.646G>A | p.Ala216Thr | missense_variant | Exon 5 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.646G>A | p.Ala216Thr | missense_variant | Exon 5 of 34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.646G>A | non_coding_transcript_exon_variant | Exon 5 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes AF: 0.000742 AC: 113AN: 152246Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000375 AC: 90AN: 240270Hom.: 0 AF XY: 0.000335 AC XY: 44AN XY: 131246
GnomAD4 exome AF: 0.000203 AC: 295AN: 1452890Hom.: 2 Cov.: 31 AF XY: 0.000192 AC XY: 139AN XY: 723034
GnomAD4 genome AF: 0.000748 AC: 114AN: 152364Hom.: 1 Cov.: 32 AF XY: 0.000859 AC XY: 64AN XY: 74502
ClinVar
Submissions by phenotype
not provided Benign:6
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MYBPC3: BP4 -
See Variant Classification Assertion Criteria. -
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Primary familial hypertrophic cardiomyopathy Uncertain:2
Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
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not specified Benign:2
proposed classification - variant undergoing re-assessment, contact laboratory -
Variant summary: MYBPC3 c.646G>A (p.Ala216Thr) results in a non-conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 240462 control chromosomes, predominantly at a frequency of 0.0027 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.646G>A has been reported in the literature in individuals affected with Cardiomyopathy however, without strong evidence for pathogenicity (example: Bick_2012, Pugh_2014). Co-occurrence with another pathogenic variant has been reported (MYBPC3 c.772G>A , p.E258K), providing supporting evidence for a benign role (Nunez_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=6) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Cardiomyopathy Benign:2
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Hypertrophic cardiomyopathy Benign:2
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Left ventricular noncompaction 10 Benign:1
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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Hypertrophic cardiomyopathy 4 Benign:1
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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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