2-178773852-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6
The NM_001267550.2(TTN):c.7316G>A(p.Arg2439His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2439C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.7316G>A | p.Arg2439His | missense_variant | 31/363 | ENST00000589042.5 | |
TTN | NM_133379.5 | c.7316G>A | p.Arg2439His | missense_variant | 31/46 | ENST00000360870.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.7316G>A | p.Arg2439His | missense_variant | 31/363 | 5 | NM_001267550.2 | P1 | |
TTN | ENST00000360870.10 | c.7316G>A | p.Arg2439His | missense_variant | 31/46 | 5 | NM_133379.5 | ||
TTN-AS1 | ENST00000659121.1 | n.1654-375C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000919 AC: 23AN: 250304Hom.: 0 AF XY: 0.0000813 AC XY: 11AN XY: 135286
GnomAD4 exome AF: 0.000183 AC: 268AN: 1461790Hom.: 0 Cov.: 33 AF XY: 0.000190 AC XY: 138AN XY: 727204
GnomAD4 genome AF: 0.000151 AC: 23AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74298
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 12, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 24, 2015 | p.Arg2439His in exon 31 of TTN: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, 5 mammals (Chinese hamster, golden hamster, naked mole-rat, cape golden mol e and dolphin) have a histidine (His) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has been identified in 2/10172 Af rican and 9/65986 European chromosomes by the Exome Aggregation Consortium (ExAC , http://exac.broadinstitute.org; dbSNP rs142129359). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 14, 2020 | 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