rs374419129
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6
The NM_001267550.2(TTN):āc.44423A>Cā(p.Lys14808Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,612,336 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001267550.2 missense, splice_region
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.44423A>C | p.Lys14808Thr | missense_variant, splice_region_variant | 240/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.44423A>C | p.Lys14808Thr | missense_variant, splice_region_variant | 240/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.502+31621T>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000444 AC: 11AN: 247552Hom.: 0 AF XY: 0.0000596 AC XY: 8AN XY: 134332
GnomAD4 exome AF: 0.0000459 AC: 67AN: 1460140Hom.: 1 Cov.: 30 AF XY: 0.0000523 AC XY: 38AN XY: 726326
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74394
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 01, 2017 | p.Lys12240Thr in exon 189 of TTN: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, 5 mammals (bushbaby, naked mole rat, bat, microbat, platypus) have a thre onine (Thr) at this position. It has been identified in 7/34274 Latino chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/ ; dbSNP rs374419129). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 31, 2016 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 19, 2017 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 23, 2021 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 30, 2019 | 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