15-43601535-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153700.2(STRC):c.4562G>A(p.Arg1521Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 1,613,514 control chromosomes in the GnomAD database, including 3,329 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1521W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.041 ( 225 hom., cov: 29)

Exomes 𝑓: 0.054 ( 3104 hom. )

Consequence

STRC
NM_153700.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0120

Publications

6 publications found

Variant links:

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]

STRC links:

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]

CKMT1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018331409).

BP6

Variant 15-43601535-C-T is Benign according to our data. Variant chr15-43601535-C-T is described in ClinVar as Benign. ClinVar VariationId is 165304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2 link	c.4562G>A	p.Arg1521Gln	missense_variant	Exon 24 of 29	ENST00000450892.7	NP_714544.1	Q7RTU9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7 link	c.4562G>A	p.Arg1521Gln	missense_variant	Exon 24 of 29	5	NM_153700.2	ENSP00000401513.2		Q7RTU9

Frequencies

GnomAD3 genomes

AF:

0.0412

AC:

6249

AN:

151832

Hom.:

225

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00990

Gnomad AMI

AF:

0.0751

Gnomad AMR

AF:

0.0301

Gnomad ASJ

AF:

0.0791

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.0291

Gnomad FIN

AF:

0.0758

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0583

Gnomad OTH

AF:

0.0461

GnomAD2 exomes

AF:

0.0459

AC:

11537

AN:

251130

AF XY:

0.0471

show subpopulations

Gnomad AFR exome

AF:

0.00964

Gnomad AMR exome

AF:

0.0257

Gnomad ASJ exome

AF:

0.0767

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.0704

Gnomad NFE exome

AF:

0.0601

Gnomad OTH exome

AF:

0.0502

GnomAD4 exome

AF:

0.0544

AC:

79437

AN:

1461564

Hom.:

3104

Cov.:

AF XY:

0.0540

AC XY:

39231

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.00887

AC:

297

AN:

33478

American (AMR)

AF:

0.0272

AC:

1214

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0750

AC:

1959

AN:

26128

East Asian (EAS)

AF:

0.000605

AC:

AN:

39692

South Asian (SAS)

AF:

0.0371

AC:

3200

AN:

86244

European-Finnish (FIN)

AF:

0.0653

AC:

3485

AN:

53386

Middle Eastern (MID)

AF:

0.0940

AC:

542

AN:

5764

European-Non Finnish (NFE)

AF:

0.0590

AC:

65639

AN:

1111780

Other (OTH)

AF:

0.0510

AC:

3077

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

4095

8189

12284

16378

20473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2370

4740

7110

9480

11850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0411

AC:

6248

AN:

151950

Hom.:

225

Cov.:

AF XY:

0.0419

AC XY:

3108

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.00987

AC:

409

AN:

41438

American (AMR)

AF:

0.0301

AC:

459

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0791

AC:

274

AN:

3464

East Asian (EAS)

AF:

0.000774

AC:

AN:

5168

South Asian (SAS)

AF:

0.0291

AC:

140

AN:

4814

European-Finnish (FIN)

AF:

0.0758

AC:

800

AN:

10552

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0584

AC:

3965

AN:

67936

Other (OTH)

AF:

0.0456

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

298

596

894

1192

1490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0473

Hom.:

205

Bravo

AF:

0.0365

TwinsUK

AF:

0.0647

AC:

240

ALSPAC

AF:

0.0576

AC:

222

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.0606

AC:

521

ExAC

AF:

0.0465

AC:

5645

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0593

EpiControl

AF:

0.0577

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg1521Gln in Exon 24 of STRC: This variant is not expected to have clinical sig nificance because it has been identified in 6.0% (422/7018) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs74643365). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.044

T;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.67

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.0

PhyloP100

0.012

PrimateAI

Benign

0.43

PROVEAN

Benign

0.16

N;N

REVEL

Benign

0.063

Sift

Benign

0.31

T;T

Sift4G

Benign

0.57

T;T

Polyphen

0.0010

B;P

Vest4

0.20

ClinPred

0.0063

GERP RS

1.7

Varity_R

0.061

gMVP

0.13

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over