rs147447264

Positions:

• chr15-43603388-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 15/19 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
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.0870

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 -10 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 id is 227969.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-43603388-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STRC	NM_153700.2	c.4399G>A	p.Val1467Ile	missense_variant	23/29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.4399G>A	p.Val1467Ile	missense_variant	23/29	5	NM_153700.2	ENSP00000401513	P2

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152020 Hom.: 4 Cov.: 31

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

GnomAD3 exomes AF: 0.000975 AC: 245 AN: 251310 Hom.: 2 AF XY: 0.00101 AC XY: 137 AN XY: 135832

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 SAS exome AF: 0.0000653

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.: 12 Cov.: 32 AF XY: 0.00114 AC XY: 827 AN XY: 727106

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00188

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000664 AC: 101 AN: 152138 Hom.: 4 Cov.: 31 AF XY: 0.000592 AC XY: 44 AN XY: 74370

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.000706

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000923 AC: 112

EpiCase AF: 0.00158

EpiControl AF: 0.00154

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 17, 2015

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.6
DANN	Benign	0.66
DEOGEN2	Benign	0.047	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.15	N;N
REVEL	Benign	0.10
Sift	Benign	0.98	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.087
MVP		0.34
ClinPred		0.0033	T
GERP RS		-0.17
Varity_R		0.025
gMVP		0.097

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

LitVar

Other links and lift over

dbSNP: rs147447264; hg19: chr15-43895586;