15-43600610-T-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_153700.2(STRC):c.4917A>C(p.Leu1639=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 151,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0019 (29 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0820

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-43600610-T-G is Benign according to our data. Variant chr15-43600610-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 805531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43600610-T-G is described in Lovd as [Likely_pathogenic].
• BP7: Synonymous conserved (PhyloP=0.082 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.4917A>C	p.Leu1639=	synonymous_variant	26/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.4917A>C	p.Leu1639=	synonymous_variant	26/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 265 AN: 151156 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000558

Gnomad AMI AF: 0.00225

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00343

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00118 AC: 297 AN: 251056 Hom.: 5 AF XY: 0.00120 AC XY: 163 AN XY: 135702

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000985

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00114

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00185 AC: 2696 AN: 1454202 Hom.: 29 Cov.: 32 AF XY: 0.00180 AC XY: 1304 AN XY: 722832

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000725

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00218

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.00175 AC: 264 AN: 151276 Hom.: 0 Cov.: 26 AF XY: 0.00151 AC XY: 112 AN XY: 73938

Gnomad4 AFR AF: 0.000556

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00321

Gnomad4 FIN AF: 0.0000949

Gnomad4 NFE AF: 0.00278

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00167 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	STRC: BP4, BP7, BS2 -

Autosomal recessive nonsyndromic hearing loss 16 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Autosomal recessive nonsyndromic hearing loss 16;C1970187:Deafness-infertility syndrome;C2751811:Spermatogenic failure 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	4.9
Dann	Benign	0.66

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

Other links and lift over

dbSNP: rs2860666; hg19: chr15-43892808;