15-43600227-G-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_153700.2(STRC):c.5060C>A(p.Ala1687Asp) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000028 ( 0 hom., cov: 23)
Exomes 𝑓: 0.000018 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
STRC
NM_153700.2 missense
NM_153700.2 missense
Scores
8
8
2
Clinical Significance
Conservation
PhyloP100: 7.09
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 Uncertain_significance. Variant got 2 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.856
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
STRC | NM_153700.2 | c.5060C>A | p.Ala1687Asp | missense_variant | 27/29 | ENST00000450892.7 | NP_714544.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STRC | ENST00000450892.7 | c.5060C>A | p.Ala1687Asp | missense_variant | 27/29 | 5 | NM_153700.2 | ENSP00000401513 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 4AN: 144660Hom.: 0 Cov.: 23 FAILED QC
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GnomAD4 exome AF: 0.0000177 AC: 21AN: 1187704Hom.: 0 Cov.: 17 AF XY: 0.0000168 AC XY: 10AN XY: 595412
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GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000277 AC: 4AN: 144660Hom.: 0 Cov.: 23 AF XY: 0.0000143 AC XY: 1AN XY: 70046
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 16 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Deafness, autosomal recessive 16 (MIM#603720). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to aspartic acid. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (v3 filtered out: 4 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2 highest count: 1 heterozygote, 0 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. The p.(Ala1687Gly) and p.(Ala1687Thr) variants are both listed in the Deafness Variation Database as VUSs based on in silico predictions, however no clinical information was provided. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant was listed in the Deafness Variation Database as pathogenic. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant inferred to be in trans with a pathogenic heterozygous deletion in a recessive disease. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of relative solvent accessibility (P = 0.0479);.;
MVP
ClinPred
D
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