15-43600649-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153700.2(STRC):c.4878C>G(p.Leu1626=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,611,690 control chromosomes in the GnomAD database, including 22,363 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (6089 hom., cov: 28)
  • Exomes 𝑓: 0.12 (16274 hom.)
• Consequence: STRC NM_153700.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.02

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]

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 15-43600649-G-C is Benign according to our data. Variant chr15-43600649-G-C is described in ClinVar as [Benign]. Clinvar id is 178634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43600649-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.482 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.4878C>G	p.Leu1626=	synonymous_variant	26/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.4878C>G	p.Leu1626=	synonymous_variant	26/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33399 AN: 151554 Hom.: 6075 Cov.: 28

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0937

Gnomad OTH AF: 0.195

GnomAD3 exomes AF: 0.160 AC: 40118 AN: 250578 Hom.: 5021 AF XY: 0.152 AC XY: 20564 AN XY: 135478

Gnomad AFR exome AF: 0.491

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.189

Gnomad EAS exome AF: 0.288

Gnomad SAS exome AF: 0.180

Gnomad FIN exome AF: 0.0387

Gnomad NFE exome AF: 0.0964

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.120 AC: 174889 AN: 1460020 Hom.: 16274 Cov.: 34 AF XY: 0.120 AC XY: 87310 AN XY: 726308

Gnomad4 AFR exome AF: 0.513

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.189

Gnomad4 EAS exome AF: 0.276

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.0404

Gnomad4 NFE exome AF: 0.0956

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.221 AC: 33458 AN: 151670 Hom.: 6089 Cov.: 28 AF XY: 0.217 AC XY: 16107 AN XY: 74154

Gnomad4 AFR AF: 0.488

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.275

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.0937

Gnomad4 OTH AF: 0.198

Alfa AF: 0.164 Hom.: 645

Bravo AF: 0.248

EpiCase AF: 0.107

EpiControl AF: 0.105

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Sep 28, 2013	Leu1626Leu in Exon 26 of STRC: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 46.0% (1721/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12438025). -

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
BayesDel_noAF	Benign	-0.54
Cadd	Benign	6.3
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12438025; hg19: chr15-43892847; COSMIC: COSV55852439; COSMIC: COSV55852439;