15-43604408-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM5PP5BP4BS2_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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1391C) has been classified as Likely pathogenic.

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:2

Conservation

PhyloP100: 1.95

Publications

4 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-43604408-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 517451.

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 VariationId is 165311.

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 rank	MANE	Protein	UniProt
STRC	NM_153700.2 link	c.4171C>G	p.Arg1391Gly	missense_variant	Exon 21 of 29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7 link	c.4171C>G	p.Arg1391Gly	missense_variant	Exon 21 of 29	5	NM_153700.2	ENSP00000401513.2

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

GnomAD2 exomes

AF:

0.000129

AC:

AN:

193244

AF XY:

0.0000867

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 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

African (AFR)

AF:

0.00

AC:

AN:

33084

American (AMR)

AF:

0.0000241

AC:

AN:

41492

Ashkenazi Jewish (ASJ)

AF:

0.00300

AC:

AN:

25626

East Asian (EAS)

AF:

0.00

AC:

AN:

39154

South Asian (SAS)

AF:

0.00

AC:

AN:

83732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51786

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.0000110

AC:

AN:

1095548

Other (OTH)

AF:

0.000236

AC:

AN:

59266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

151698

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

74054

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41312

American (AMR)

AF:

0.00

AC:

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.00462

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67904

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 16

Pathogenic:2

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 07, 2021

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

not provided

Pathogenic:1Uncertain:1

Feb 25, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PM3_strong -

Dec 16, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 10, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 19, 2016

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Congenital, mild-moderate HL -

Rare genetic deafness

Pathogenic:1

Jan 10, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Autosomal recessive nonsyndromic hearing loss 16;C1970187:Deafness-infertility syndrome;C2751811:Spermatogenic failure 7

Uncertain:1

Feb 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

(source)

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

PhyloP100

1.9

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

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over