rs144948296
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_153700.2(STRC):c.4027C>T(p.Gln1343*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,613,618 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000099 ( 1 hom. )
Consequence
STRC
NM_153700.2 stop_gained
NM_153700.2 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 1.30
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-43604750-G-A is Pathogenic according to our data. Variant chr15-43604750-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43604750-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152000Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000183 AC: 46AN: 250926Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135648
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GnomAD4 exome AF: 0.0000985 AC: 144AN: 1461500Hom.: 1 Cov.: 33 AF XY: 0.0000935 AC XY: 68AN XY: 727064
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GnomAD4 genome 0.0000197 AC: 3AN: 152118Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74360
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 16 Pathogenic:5
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Jun 18, 2024 | The STRC c.4027C>T (p.Gln1343*) variant has been reported in five individuals affected with hearing loss (Amr SS et al., PMID: 29339441; Frykholm C et al., PMID:30250054; Mandelker D et al., PMID:25157971). Of those individuals, three were compound heterozygous for the variant and a pathogenic or likely pathogenic variant confirmed in trans (Amr SS et al., PMID: 29339441; Frykholm C et al., PMID:30250054; Mandelker D et al., PMID:25157971). Two individuals were homozygous for the variant (Frykholm C et al., PMID:30250054). This variant has been reported in the ClinVar database as a pathogenic variant by three submitters and as likely pathogenic by two submitters. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.0362% in the European non-Finnish population. This variant leads to a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | May 18, 2017 | - - |
| Pathogenic, criteria provided, single submitter | research | Research Group Niklas Dahl, Uppsala University | Dec 11, 2017 | We identified a family segregating a homozygous STRC stop variant [c.4027C>T, p.(Q1343*)] identified by exome sequencing in two siblings and their first cousin with childhood onset of episodic vertigo. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 21, 2019 | - - |
Rare genetic deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 04, 2016 | The p.Gln1343X variant in STRC has been identified in one individual with hearin g loss who was compound heterozygous for a second pathogenic STRC variant (Mande lker 2014). This nonsense variant leads to a premature termination codon at posi tion 1343 which is predicted to lead to a truncated or absent protein. Loss of f unction of the STRC gene is an established disease mechanism in autosomal recess ive nonsyndromic sensorineural hearing loss (SNHL). In summary, this variant me ets criteria to be classified as pathogenic for SNHL in an autosomal recessive m anner based on the predicted impact of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
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