15-43613218-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_153700.2(STRC):c.2494C>T(p.Arg832Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R832Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000042 ( 0 hom., cov: 6)

Exomes 𝑓: 0.000045 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STRC
NM_153700.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.42

Publications

1 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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 16
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

STRC links:

ENSG00000309475 (HGNC:):

ENSG00000309475 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2 link	c.2494C>T	p.Arg832Trp	missense_variant	Exon 8 of 29	ENST00000450892.7	NP_714544.1	Q7RTU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7 link	c.2494C>T	p.Arg832Trp	missense_variant	Exon 8 of 29	5	NM_153700.2	ENSP00000401513.2		Q7RTU9

Frequencies

GnomAD3 genomes

AF:

0.0000421

AC:

AN:

47476

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000355

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000403

AC:

AN:

49592

AF XY:

0.0000398

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000988

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000574

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000449

AC:

AN:

267192

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

145166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

5446

American (AMR)

AF:

0.000267

AC:

AN:

14972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6028

East Asian (EAS)

AF:

0.00

AC:

AN:

12376

South Asian (SAS)

AF:

0.00

AC:

AN:

43558

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11472

Middle Eastern (MID)

AF:

0.00

AC:

AN:

840

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

159964

Other (OTH)

AF:

0.000160

AC:

AN:

12536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.404

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000421

AC:

AN:

47476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

22156

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

4994

American (AMR)

AF:

0.000209

AC:

AN:

4786

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1354

East Asian (EAS)

AF:

0.00

AC:

AN:

1906

South Asian (SAS)

AF:

0.00

AC:

AN:

1236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.0000355

AC:

AN:

28172

Other (OTH)

AF:

0.00

AC:

AN:

596

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Apr 12, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 21, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in a patient with bilateral sensorineural hearing loss who also harbored a gene conversion event involving the STRC gene on the opposite allele (in trans) in the published literature (PMID: 36086952); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36086952) -

May 13, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg832Trp variant in STRC has been identified by our laboratory in two individuals with hearing loss who also had a STRC/CATSPER2 deletion. This variant has been identified in 0.0001% (1/10124) Latino/Admixed American chromosomes and 0.006% (1/1742) other chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, these frequency estimates may not be reliable due to low coverage of this region. Computational prediction tools and conservation analyses suggest that the Arg832Trp variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_Strong, PP3. -

Inborn genetic diseases

Uncertain:1

Aug 04, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2494C>T (p.R832W) alteration is located in exon 8 (coding exon 8) of the STRC gene. This alteration results from a C to T substitution at nucleotide position 2494, causing the arginine (R) at amino acid position 832 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

T;.

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.91

D;T

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Uncertain

-0.17

PhyloP100

2.4

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-2.5

N;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.49

MutPred

0.59

Loss of disorder (P = 0.0093);.;

MVP

0.87

ClinPred

0.40

GERP RS

1.8

Varity_R

0.23

gMVP

0.71

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over