15-43600074-T-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The NM_153700.2(STRC):āc.5125A>Gā(p.Thr1709Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.00018 ( 0 hom., cov: 22)
Exomes š: 0.000054 ( 6 hom. )
Failed GnomAD Quality Control
Consequence
STRC
NM_153700.2 missense
NM_153700.2 missense
Scores
2
8
8
Clinical Significance
Conservation
PhyloP100: 3.07
Genes affected
STRC (HGNC:16035): (stereocilin) This gene encodes a protein that is associated with the hair bundle of the sensory hair cells in the inner ear. The hair bundle is composed of stiff microvilli called stereocilia and is involved with mechanoreception of sound waves. This gene is part of a tandem duplication on chromosome 15; the second copy is a pseudogene. Mutations in this gene cause autosomal recessive non-syndromic deafness. [provided by RefSeq, Jul 2008]
CKMT1B (HGNC:1995): (creatine kinase, mitochondrial 1B) Mitochondrial creatine (MtCK) kinase is responsible for the transfer of high energy phosphate from mitochondria to the cytosolic carrier, creatine. It belongs to the creatine kinase isoenzyme family. It exists as two isoenzymes, sarcomeric MtCK and ubiquitous MtCK, encoded by separate genes. Mitochondrial creatine kinase occurs in two different oligomeric forms: dimers and octamers, in contrast to the exclusively dimeric cytosolic creatine kinase isoenzymes. Many malignant cancers with poor prognosis have shown overexpression of ubiquitous mitochondrial creatine kinase; this may be related to high energy turnover and failure to eliminate cancer cells via apoptosis. Ubiquitous mitochondrial creatine kinase has 80% homology with the coding exons of sarcomeric mitochondrial creatine kinase. Two genes located near each other on chromosome 15 have been identified which encode identical mitochondrial creatine kinase proteins. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PP5
Variant 15-43600074-T-C is Pathogenic according to our data. Variant chr15-43600074-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43600074-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STRC | NM_153700.2 | c.5125A>G | p.Thr1709Ala | missense_variant | 28/29 | ENST00000450892.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STRC | ENST00000450892.7 | c.5125A>G | p.Thr1709Ala | missense_variant | 28/29 | 5 | NM_153700.2 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 27AN: 151264Hom.: 0 Cov.: 22 FAILED QC
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000541 AC: 79AN: 1460532Hom.: 6 Cov.: 32 AF XY: 0.0000647 AC XY: 47AN XY: 726562
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GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000178 AC: 27AN: 151382Hom.: 0 Cov.: 22 AF XY: 0.000216 AC XY: 16AN XY: 73962
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 21, 2022 | PM2_supporting, PM3 - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 02, 2023 | The p.Thr1709Ala variant in STRC has been reported in 4 individuals with hearing loss, all of whom carried a second pathogenic STRC variant (Vona 2015, Kim 2016, Baux 2017, LMM data). It has also been identified in 0.06% (12/19778) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP3. (This variant did not meet the variant calling quality criteria, and was included because it has been previously reported as a clinically significant variant.) - |
STRC-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 18, 2024 | The STRC c.5125A>G variant is predicted to result in the amino acid substitution p.Thr1709Ala. This variant has been reported along with another potentially pathogenic variant in three patients with hearing loss. Although two of these studies confirmed the location of this variant in the STRC functional gene, further evidence of pathogenicity was not presented (Vona et al. 2015. PubMed ID: 26011646; Kim et al. 2016. PubMed ID: 27057829; Kim et al. 2020. PubMed ID: 32203226; Baux et al. 2017. PubMed ID: 29196752). This variant in exon 28 corresponds to a known STRCP1 pseudogene variant, and therefore presence of this variant in the functional gene (as in this patient) may be indicative of a large deletion or gene conversion event on the same allele. While we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Pathogenic
D;D
Polyphen
D;P
Vest4
MutPred
Loss of loop (P = 0.1242);.;
MVP
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at