15-43600664-G-C

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.4863C>G(p.Leu1621=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,612,422 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (5 hom., cov: 28)
  • Exomes 𝑓: 0.0019 (49 hom.)
• Consequence: STRC NM_153700.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.53

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=-0.56).
• BP6: Variant 15-43600664-G-C is Benign according to our data. Variant chr15-43600664-G-C is described in ClinVar as [Benign]. Clinvar id is 165299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43600664-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0045 (684/151948) while in subpopulation SAS AF= 0.0217 (104/4796). AF 95% confidence interval is 0.0183. There are 5 homozygotes in gnomad4. There are 328 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.4863C>G	p.Leu1621=	synonymous_variant	26/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.4863C>G	p.Leu1621=	synonymous_variant	26/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes AF: 0.00452 AC: 686 AN: 151832 Hom.: 5 Cov.: 28

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00267 AC: 669 AN: 250786 Hom.: 14 AF XY: 0.00281 AC XY: 381 AN XY: 135510

Gnomad AFR exome AF: 0.00921

Gnomad AMR exome AF: 0.000984

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00937

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00187 AC: 2737 AN: 1460474 Hom.: 49 Cov.: 34 AF XY: 0.00214 AC XY: 1558 AN XY: 726438

Gnomad4 AFR exome AF: 0.00831

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.00482

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0109

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00450 AC: 684 AN: 151948 Hom.: 5 Cov.: 28 AF XY: 0.00442 AC XY: 328 AN XY: 74262

Gnomad4 AFR AF: 0.0107

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0217

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00120 Hom.: 0

EpiCase AF: 0.00115

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 11, 2013

Leu1621Leu in Exon 26 of STRC: This variant is not expected to have clinical sig nificance because it has been observed in 0.5% (23/4410) of African American chr omosomes by the NHLBI Exome Sequencing Project, it does not alter an amino acid residue, and it is not located within the splice consensus sequence (http://evs. gs.washington.edu/EVS/; dbSNP rs139683375). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

STRC: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	2.0
Dann	Benign	0.68

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: rs139683375; hg19: chr15-43892862;