rs138763871

chr15-43601536-G-Achr15-43601536-G-Cchr15-43601536-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_153700.2(STRC):c.4561C>T(p.Arg1521Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,611,700 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 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. R1521Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0050 ( 18 hom., cov: 29)

Exomes 𝑓: 0.0034 ( 97 hom. )

Consequence

STRC
NM_153700.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.518

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 made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073873997).

BP6

Variant 15-43601536-G-A is Benign according to our data. Variant chr15-43601536-G-A is described in ClinVar as [Benign]. Clinvar id is 165306.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-43601536-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2 linkuse as main transcript	c.4561C>T	p.Arg1521Trp	missense_variant	24/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7 linkuse as main transcript	c.4561C>T	p.Arg1521Trp	missense_variant	24/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes

AF:

0.00504

AC:

766

AN:

151914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000722

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0393

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00318

Gnomad OTH

AF:

0.00384

GnomAD3 exomes

AF:

0.00491

AC:

1234

AN:

251096

Hom.:

AF XY:

0.00488

AC XY:

663

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.00253

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.0365

Gnomad NFE exome

AF:

0.00304

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00337

AC:

4919

AN:

1459668

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

2467

AN XY:

726172

show subpopulations

Gnomad4 AFR exome

AF:

0.00320

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.0358

Gnomad4 NFE exome

AF:

0.00237

Gnomad4 OTH exome

AF:

0.00302

GnomAD4 genome

AF:

0.00503

AC:

765

AN:

152032

Hom.:

Cov.:

AF XY:

0.00654

AC XY:

486

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00268

Gnomad4 AMR

AF:

0.000721

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0393

Gnomad4 NFE

AF:

0.00316

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.00253

Hom.:

Bravo

AF:

0.00213

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00451

AC:

547

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00241

EpiControl

AF:

0.00244

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 03, 2015

p.Arg1521Trp in exon 24 of STRC: This variant is not expected to have clinical s ignificance because it has been identified in 3.9% (254/6588) of Finnish chromos omes including 8 homozygotes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs138763871), and the arginine (Arg) residue at po sition 1521 is not conserved through species. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0074

T;T

MetaSVM

Benign

-0.63

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.3

N;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.99

D;D

Vest4

0.52

MVP

0.84

ClinPred

0.020

GERP RS

0.40

Varity_R

0.095

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over