rs56385906

chr15-43610931-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_153700.2(STRC):c.3360T>C(p.Cys1120=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 146,078 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (86 hom., cov: 22)
  • Exomes 𝑓: 0.011 (2718 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.191

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-43610931-A-G is Benign according to our data. Variant chr15-43610931-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 227082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43610931-A-G is described in Lovd as [Benign]. Variant chr15-43610931-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.191 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0191 (2784/146078) while in subpopulation NFE AF= 0.031 (1996/64330). AF 95% confidence interval is 0.0299. There are 86 homozygotes in gnomad4. There are 1325 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 86 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.3360T>C	p.Cys1120=	synonymous_variant	14/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.3360T>C	p.Cys1120=	synonymous_variant	14/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2787 AN: 145958 Hom.: 86 Cov.: 22

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.0215

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0183

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.0310

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0133 AC: 3179 AN: 238230 Hom.: 326 AF XY: 0.0132 AC XY: 1690 AN XY: 128488

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.000382

Gnomad SAS exome AF: 0.00877

Gnomad FIN exome AF: 0.00754

Gnomad NFE exome AF: 0.0186

Gnomad OTH exome AF: 0.0193

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0111 AC: 15335 AN: 1381298 Hom.: 2718 Cov.: 29 AF XY: 0.0112 AC XY: 7682 AN XY: 688280

Gnomad4 AFR exome AF: 0.000906

Gnomad4 AMR exome AF: 0.00891

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00681

Gnomad4 FIN exome AF: 0.0141

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.0191 AC: 2784 AN: 146078 Hom.: 86 Cov.: 22 AF XY: 0.0185 AC XY: 1325 AN XY: 71594

Gnomad4 AFR AF: 0.00379

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.0183

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.0310

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0387 Hom.: 52

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	Jun 26, 2013	Cys1120Cys in Exon 14 of STRC: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, has been identified in 7.6% (10/132) of chromoso mes from an European American (CEU) population in 1000Genomes project (reported in Deafness Variation Database: http://deafnessvariationdatabase.org; dbSNP rs56 385906). -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2019	- -

Autosomal recessive nonsyndromic hearing loss 16 Benign:1

Likely 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
BayesDel_noAF	Benign	-0.82
Cadd	Benign	7.8
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs56385906; hg19: chr15-43903129; COSMIC: COSV70833292; COSMIC: COSV70833292;