rs56042996

chr15-43605301-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153700.2(STRC):c.3893A>G(p.His1298Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,590,212 control chromosomes in the GnomAD database, including 21,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5826 hom., cov: 30)
  • Exomes 𝑓: 0.12 (15712 hom.)
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.35

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021159947).
• BP6: Variant 15-43605301-T-C is Benign according to our data. Variant chr15-43605301-T-C is described in ClinVar as [Benign]. Clinvar id is 165312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43605301-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.3893A>G	p.His1298Arg	missense_variant	19/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.3893A>G	p.His1298Arg	missense_variant	19/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32808 AN: 151178 Hom.: 5814 Cov.: 30

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.0402

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.0941

Gnomad OTH AF: 0.191

GnomAD3 exomes AF: 0.161 AC: 32392 AN: 200968 Hom.: 3859 AF XY: 0.154 AC XY: 16693 AN XY: 108198

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.286

Gnomad SAS exome AF: 0.179

Gnomad FIN exome AF: 0.0391

Gnomad NFE exome AF: 0.0978

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.120 AC: 172233 AN: 1438918 Hom.: 15712 Cov.: 33 AF XY: 0.120 AC XY: 85682 AN XY: 713602

Gnomad4 AFR exome AF: 0.501

Gnomad4 AMR exome AF: 0.199

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.274

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.0401

Gnomad4 NFE exome AF: 0.0963

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.217 AC: 32866 AN: 151294 Hom.: 5826 Cov.: 30 AF XY: 0.214 AC XY: 15799 AN XY: 73916

Gnomad4 AFR AF: 0.477

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.182

Gnomad4 EAS AF: 0.273

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.0402

Gnomad4 NFE AF: 0.0940

Gnomad4 OTH AF: 0.194

Alfa AF: 0.162 Hom.: 623

Bravo AF: 0.245

ESP6500AA AF: 0.451 AC: 1981

ESP6500EA AF: 0.0978 AC: 836

ExAC AF: 0.147 AC: 17652

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	His1298Arg in Exon 19 of STRC: This variant is not expected to have clinical sig nificance because it has been identified in 44.6% (1663/3728) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs2920780). -

Autosomal recessive nonsyndromic hearing loss 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.043	T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.61	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	8.2e-8	P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.098
Sift	Benign	0.22	T;T
Sift4G	Benign	0.81	T;T
Polyphen		0.0	B;B
Vest4		0.13
ClinPred		0.0040	T
GERP RS		2.9
Varity_R		0.054
gMVP		0.39

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

Other links and lift over

dbSNP: rs2920780; hg19: chr15-43897499; COSMIC: COSV68461473; COSMIC: COSV68461473;