15-43604408-G-C

Position:

chr15-43604408-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting

The NM_153700.2(STRC):c.4171C>G(p.Arg1391Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,587,048 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000072 ( 2 hom. )

Consequence

STRC
NM_153700.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 1.95

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]

STRC links:

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]

CKMT1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP5

Variant 15-43604408-G-C is Pathogenic according to our data. Variant chr15-43604408-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165311.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1, Pathogenic=1}. Variant chr15-43604408-G-C is described in Lovd as [Likely_pathogenic]. Variant chr15-43604408-G-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.22616577). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STRC	NM_153700.2 linkuse as main transcript	c.4171C>G	p.Arg1391Gly	missense_variant	21/29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7 linkuse as main transcript	c.4171C>G	p.Arg1391Gly	missense_variant	21/29	5	NM_153700.2	ENSP00000401513	P2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151698

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00462

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000129

AC:

AN:

193244

Hom.:

AF XY:

0.0000867

AC XY:

AN XY:

103866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00221

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000252

Gnomad OTH exome

AF:

0.000588

GnomAD4 exome

AF:

0.0000725

AC:

104

AN:

1435350

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

711740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000241

Gnomad4 ASJ exome

AF:

0.00300

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000110

Gnomad4 OTH exome

AF:

0.000236

GnomAD4 genome

AF:

0.000105

AC:

AN:

151698

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

74054

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00462

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000432

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000354

AC:

ExAC

AF:

0.0000923

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 16

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Jan 07, 2021	The c.4171C>G variant in the STRC gene is missense variant, which results in the substitution of an arginine residue at amino acid position 1391 for a glycine (NP_116023.2). This variant localizes to coding exon 21 of the STRC gene (29 coding exons in total; NM_032634.4). In silico predictors for this variant are not consistent: It is predicted to be neutral to protein structure and/or function by PROVEAN, but is predicted to be damaging by SIFT. This variant was reported in Genome Aggregation Database (gnomAD) with an allelic frequency of 0.0129% (25 out of 193,244 alleles). This variant is reported in ClinVar as pathogenic/likely pathogenic by three laboratories (allele ID# 165311, last accessed 8/11/2020). This variant has been reported in two Ashkenazi Jewish families with mild to moderate hearing loss: in one family, the variant was found in the homozygous state in all six affected siblings while parents were heterozygous carriers. In the second family, two affected siblings were compound heterozygous for this variant and a large deletion of the STRC gene (PMID: 22147502). Given this evidence, the c.4171C>G (p.Arg1391Gly) variant in STRC is considered likely pathogenic. Parental studies were not conducted at our laboratory, but this variant was reported to be paternally-inherited in an older sibling -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2022	PM2, PM3_strong -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 22147502) -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 10, 2023

Variant summary: STRC c.4171C>G (p.Arg1391Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 193244 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in STRC causing Nonsyndromic Hearing Loss And Deafness, Type 16 (0.00013 vs 0.0011), allowing no conclusion about variant significance. c.4171C>G has been reported in the literature in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness (Francey_2012, Sloan-Heggen_2016) and observed to segregate with disease. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22147502, 26969326). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Autosomal dominant nonsyndromic hearing loss 16

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Prof. Karen Avraham, Tel Aviv University

Feb 19, 2016

Congenital, mild-moderate HL -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 10, 2020

The p.Arg1391Gly variant in STRC has been reported in two Ashkenazi Jewish families with mild to moderate sensorineural hearing loss (Francey 2011). In one family, this variant was found in the homozygous state in all six affected siblings while unaffected parents were heterozygous for this variant. In the other family, the two affected siblings were compound heterozygous for the Arg1391Gly variant and a large deletion of the STRC gene. This variant has also been detected in 0.5% (1/182) of Ashkenazi Jewish control chromosomes by the same study (Francey 2011) and in 0.2% (20/9068) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). In summary, although additional studies are required to fully establish its clinical significance, this variant is classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PM3, PP1_Strong, BS1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

0.082

Eigen_PC

Benign

0.087

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.81

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.23

T;T

MetaSVM

Uncertain

-0.14

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.64

Sift

Benign

0.042

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.65

MVP

0.89

ClinPred

0.53

GERP RS

3.6

Varity_R

0.20

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over