15-43600074-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_153700.2(STRC):ā€‹c.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

Scores

2
8
8

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U:1

Conservation

PhyloP100: 3.07
Variant links:
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]

Genome browser will be placed here

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
STRCNM_153700.2 linkuse as main transcriptc.5125A>G p.Thr1709Ala missense_variant 28/29 ENST00000450892.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
STRCENST00000450892.7 linkuse as main transcriptc.5125A>G p.Thr1709Ala missense_variant 28/295 NM_153700.2 P2

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
27
AN:
151264
Hom.:
0
Cov.:
22
FAILED QC
Gnomad AFR
AF:
0.000171
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000132
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00137
Gnomad SAS
AF:
0.00126
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000590
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000541
AC:
79
AN:
1460532
Hom.:
6
Cov.:
32
AF XY:
0.0000647
AC XY:
47
AN XY:
726562
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000330
Gnomad4 SAS exome
AF:
0.000151
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000178
AC:
27
AN:
151382
Hom.:
0
Cov.:
22
AF XY:
0.000216
AC XY:
16
AN XY:
73962
show subpopulations
Gnomad4 AFR
AF:
0.000170
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00137
Gnomad4 SAS
AF:
0.00126
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000590
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000288
Hom.:
0

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 submitterclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 21, 2022PM2_supporting, PM3 -
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 02, 2023The 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 providedclinical testingPreventionGenetics, part of Exact SciencesJun 18, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Benign
-0.032
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
T;.
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.51
T;T
M_CAP
Pathogenic
0.71
D
MetaRNN
Uncertain
0.69
D;D
MetaSVM
Uncertain
0.17
D
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-0.50
N;N
REVEL
Uncertain
0.64
Sift
Benign
0.17
T;T
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.99
D;P
Vest4
0.43
MutPred
0.29
Loss of loop (P = 0.1242);.;
MVP
0.78
ClinPred
0.16
T
GERP RS
4.8
Varity_R
0.10
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1336307815; hg19: chr15-43892272; COSMIC: COSV55853435; COSMIC: COSV55853435; API