NM_001103.4:c.2147C>T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001103.4(ACTN2):c.2147C>T(p.Thr716Met) variant causes a missense change. The variant allele was found at a frequency of 0.000289 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T716T) has been classified as Likely benign.
Frequency
Consequence
NM_001103.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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ACTN2 | NM_001103.4 | c.2147C>T | p.Thr716Met | missense_variant | Exon 17 of 21 | ENST00000366578.6 | NP_001094.1 | |
ACTN2 | NM_001278343.2 | c.2147C>T | p.Thr716Met | missense_variant | Exon 17 of 21 | NP_001265272.1 | ||
ACTN2 | NR_184402.1 | n.2519C>T | non_coding_transcript_exon_variant | Exon 19 of 23 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000223 AC: 34AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000423 AC: 106AN: 250452Hom.: 0 AF XY: 0.000487 AC XY: 66AN XY: 135398
GnomAD4 exome AF: 0.000296 AC: 433AN: 1461830Hom.: 0 Cov.: 32 AF XY: 0.000297 AC XY: 216AN XY: 727206
GnomAD4 genome AF: 0.000223 AC: 34AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74350
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:6
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ACTN2: BS1 -
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25333069, 25611685) -
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Cardiomyopathy Uncertain:1Benign:1
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not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The p.Thr716Met var iant in ACTN2 has been previously identified by our laboratory in 4 individuals with a range of cardiac features (1 adult with HCM, 1 adult with ARVC, 1 adolesc ent with mitral valve prolapse, and 1 adult with LVH and a mildly dilated LA). I t has also been identified in 0.1% (39/66254) of European chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1939226 35). Computational prediction tools and conservation analysis do not provide str ong support for or against an impact to the protein. In summary, while the clini cal significance of the p.Thr716Met variant is uncertain, these data suggest tha t it is more likely to be benign. -
Dilated cardiomyopathy 1AA Uncertain: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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Primary familial hypertrophic cardiomyopathy Uncertain:1
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Hypertrophic cardiomyopathy 1 Uncertain:1
The ACTN2 Thr716Met variant has been previously reported to occur in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.0003, and sub-population frequency of European (non-Finnish) individuals at 0.00059 (39/66254 alleles). The variant is absent in the 1000 genomes project (http://www.1000genomes.org/). Threonine (Thr) at position 716 is relatively conserved across distantly related species, and in silico tools are supportive of a damaging effect (SIFT "deleterious"; PolyPhen2 "probably damaging"; MutationTaster "disease-causing"; CADD score = 19), however this alone cannot be considered as strong evidence for pathogenicity. We have identified the ACTN2 Thr716Met variant in a single HCM proband of European descent. The patient was diagnosed aged 50 years, with asymmetric septal hypertophy of 20mm, and no established family history of disease. Based on the limited evidence, we call this variant one of "uncertain significance". -
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1
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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