15-43600695-A-G

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.4845-13T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,579,662 control chromosomes in the GnomAD database, including 21,931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (6081 hom., cov: 28)
  • Exomes 𝑓: 0.11 (15850 hom.)
• Consequence: STRC NM_153700.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0730

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 15-43600695-A-G is Benign according to our data. Variant chr15-43600695-A-G is described in ClinVar as [Benign]. Clinvar id is 178635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43600695-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.4845-13T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.4845-13T>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_153700.2	P2

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33382 AN: 151506 Hom.: 6068 Cov.: 28

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.0403

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0936

Gnomad OTH AF: 0.195

GnomAD3 exomes AF: 0.153 AC: 37775 AN: 246558 Hom.: 4789 AF XY: 0.145 AC XY: 19271 AN XY: 133250

Gnomad AFR exome AF: 0.481

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.282

Gnomad SAS exome AF: 0.169

Gnomad FIN exome AF: 0.0375

Gnomad NFE exome AF: 0.0914

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.111 AC: 158193 AN: 1428042 Hom.: 15850 Cov.: 34 AF XY: 0.112 AC XY: 79332 AN XY: 711096

Gnomad4 AFR exome AF: 0.510

Gnomad4 AMR exome AF: 0.190

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.273

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.0396

Gnomad4 NFE exome AF: 0.0863

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.221 AC: 33439 AN: 151620 Hom.: 6081 Cov.: 28 AF XY: 0.217 AC XY: 16095 AN XY: 74142

Gnomad4 AFR AF: 0.488

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.277

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.0403

Gnomad4 NFE AF: 0.0936

Gnomad4 OTH AF: 0.199

Alfa AF: 0.105 Hom.: 327

Bravo AF: 0.248

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	4845-13T>C in Intron 25 of STRC: This variant is not expected to have clinical s ignificance because it has been identified in 42.3% (1581/3738) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs12437957). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Autosomal recessive nonsyndromic hearing loss 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	6.7
Dann	Benign	0.56

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: rs12437957; hg19: chr15-43892893; COSMIC: COSV55853095; COSMIC: COSV55853095;