15-43599999-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_153700.2(STRC):c.5200T>C(p.Trp1734Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,440,188 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 21)
  • Exomes 𝑓: 0.0017 (22 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.10

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014477223).
• BP6: Variant 15-43599999-A-G is Benign according to our data. Variant chr15-43599999-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 505196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43599999-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.5200T>C	p.Trp1734Arg	missense_variant	28/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.5200T>C	p.Trp1734Arg	missense_variant	28/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 171 AN: 143872 Hom.: 1 Cov.: 21

Gnomad AFR AF: 0.00122

Gnomad AMI AF: 0.0145

Gnomad AMR AF: 0.000422

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00158

Gnomad OTH AF: 0.000517

GnomAD3 exomes AF: 0.000955 AC: 192 AN: 201040 Hom.: 2 AF XY: 0.000922 AC XY: 99 AN XY: 107324

Gnomad AFR exome AF: 0.00153

Gnomad AMR exome AF: 0.000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000559

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00168 AC: 2424 AN: 1440188 Hom.: 22 Cov.: 29 AF XY: 0.00167 AC XY: 1200 AN XY: 716502

Gnomad4 AFR exome AF: 0.000785

Gnomad4 AMR exome AF: 0.000456

Gnomad4 ASJ exome AF: 0.0000774

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.0000565

Gnomad4 NFE exome AF: 0.00212

Gnomad4 OTH exome AF: 0.000838

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00119 AC: 171 AN: 143980 Hom.: 1 Cov.: 21 AF XY: 0.00116 AC XY: 81 AN XY: 69778

Gnomad4 AFR AF: 0.00122

Gnomad4 AMR AF: 0.000422

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00158

Gnomad4 OTH AF: 0.000512

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.00129

ESP6500AA AF: 0.000914 AC: 4

ESP6500EA AF: 0.00117 AC: 10

ExAC AF: 0.000769 AC: 93

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	STRC: BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 21, 2016

p.Trp1734Arg in exon 28 of STRC: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (53/20438) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200770543). -

Autosomal recessive nonsyndromic hearing loss 16 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.054	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.23
Sift	Benign	0.055	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.10	B;B
Vest4		0.60
MutPred		0.35		Loss of helix (P = 0.0104);.;
MVP		0.66
ClinPred		0.012	T
GERP RS		2.4
Varity_R		0.18
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs200770543; hg19: chr15-43892197;