rs12437957

Variant names:

• chr15-43600695-A-G
• rs12437957
• NM_153700.2:c.4845-13T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-43600695-A-G
• chr15-43600695-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153700.2(STRC):​c.4845-13T>C variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0730
• Publications: 10 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 178635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
STRC	NM_153700.2	c.4845-13T>C		intron_variant	Intron 25 of 28	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.4845-13T>C		intron_variant	Intron 25 of 28	5	NM_153700.2	ENSP00000401513.2

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

GnomAD2 exomes AF: 0.153 AC: 37775 AN: 246558 AF XY: 0.145

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.510 AC: 15930 AN: 31226

American (AMR) AF: 0.190 AC: 8213 AN: 43272

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 4672 AN: 25604

East Asian (EAS) AF: 0.273 AC: 10728 AN: 39238

South Asian (SAS) AF: 0.167 AC: 14037 AN: 83866

European-Finnish (FIN) AF: 0.0396 AC: 2112 AN: 53306

Middle Eastern (MID) AF: 0.129 AC: 723 AN: 5596

European-Non Finnish (NFE) AF: 0.0863 AC: 93760 AN: 1086910

Other (OTH) AF: 0.136 AC: 8018 AN: 59024

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.488 AC: 20101 AN: 41174

American (AMR) AF: 0.196 AC: 2988 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 636 AN: 3460

East Asian (EAS) AF: 0.277 AC: 1428 AN: 5158

South Asian (SAS) AF: 0.195 AC: 938 AN: 4804

European-Finnish (FIN) AF: 0.0403 AC: 425 AN: 10558

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.0936 AC: 6356 AN: 67916

Other (OTH) AF: 0.199 AC: 418 AN: 2104

Alfa AF: 0.105 Hom.: 327

Bravo AF: 0.248

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 16 Benign:1

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Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	6.7
DANN	Benign	0.56
PhyloP100		-0.073
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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