rs147447264

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_153700.2(STRC):c.4399G>A(p.Val1467Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,688 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00066 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 12 hom. )

Consequence

STRC
NM_153700.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0870

Publications

3 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015036613).

BP6

Variant 15-43603388-C-T is Benign according to our data. Variant chr15-43603388-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 227969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2 link	c.4399G>A	p.Val1467Ile	missense_variant	Exon 23 of 29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7 link	c.4399G>A	p.Val1467Ile	missense_variant	Exon 23 of 29	5	NM_153700.2	ENSP00000401513.2

Frequencies

GnomAD3 genomes

AF:

0.000664

AC:

101

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000975

AC:

245

AN:

251310

AF XY:

0.00101

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00165

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00111

AC:

1626

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

827

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33476

American (AMR)

AF:

0.000559

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00133

AC:

1484

AN:

1111890

Other (OTH)

AF:

0.000662

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

108

216

323

431

539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.000664

AC:

101

AN:

152138

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0000964

AC:

AN:

41506

American (AMR)

AF:

0.000262

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00125

AC:

AN:

67978

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00109

Hom.:

Bravo

AF:

0.000706

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000923

AC:

112

EpiCase

AF:

0.00158

EpiControl

AF:

0.00154

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:1

Apr 17, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Val1467Ile in exon 23 of STRC: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 19 mammals have an isoleucine (Ile) at this position despite high nearby a mino acid conservation. Additional computational prediction tools do not suggest a high likelihood of impact to the protein. The variant has also been identifie d in 0.2% (105/66670) of European chromosomes including 1 homozygote by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs14744726 4).

Autosomal recessive nonsyndromic hearing loss 16;C1970187:Deafness-infertility syndrome;C2751811:Spermatogenic failure 7

Benign:1

Feb 07, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.6

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.047

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

.;.

PhyloP100

-0.087

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.15

N;N

REVEL

Benign

0.10

Sift

Benign

0.98

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.087

ClinPred

0.0033

GERP RS

-0.17

Varity_R

0.025

gMVP

0.097

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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