chr15-43600609-G-A

Position:

• chr15-43600609-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_153700.2(STRC):​c.4918C>T​(p.Leu1640Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,606,082 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1640R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0018 (29 hom.)
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:2
• Conservation: PhyloP100: 2.79

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08820775).
• BS2: High Homozygotes in GnomAdExome4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.4918C>T	p.Leu1640Phe	missense_variant	26/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.4918C>T	p.Leu1640Phe	missense_variant	26/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 265 AN: 151408 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000557

Gnomad AMI AF: 0.00335

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00362

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00118 AC: 296 AN: 251078 Hom.: 5 AF XY: 0.00119 AC XY: 162 AN XY: 135708

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: 0.0000657

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00185 AC: 2686 AN: 1454554 Hom.: 29 Cov.: 32 AF XY: 0.00180 AC XY: 1300 AN XY: 723052

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: 0.000701

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00217

Gnomad4 OTH exome AF: 0.00175

GnomAD4 genome AF: 0.00174 AC: 264 AN: 151528 Hom.: 0 Cov.: 26 AF XY: 0.00148 AC XY: 110 AN XY: 74084

Gnomad4 AFR AF: 0.000555

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00341

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000452 Hom.: 0

ExAC AF: 0.00108 AC: 131

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	STRC: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 04, 2017	The p.Leu1640Phe variant (rs727503441) has previously been associated with congenital moderate hearing loss in several patients who also carried heterozygous deletions of STRC (Mandelker 2014 and Vona 2015). It has also been reported to ClinVar with the classification of uncertain significance. The c.4917_4918delinsCT variant is listed in the Genome Aggregation Database (gnomAD) browser as two separate variants, c.4917A>C and c.4918C>T (rs2860666 and rs2920791), but viewable data on the gnomAD website indicate that both variants are inherited together and have an overall population frequency of 0.118 percent (identified on 289 out of 245,896 chromosomes, including 5 homozygotes). Individuals with hearing loss are not explicitly excluded from the gnomAD data set; therefore, the hearing ability of the 5 homozygous individuals in gnomAD is unknown. The leucine at position 1640 is moderately conserved (considering 11 species) (Alamut v.2.8.1) and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: possibly damaging). -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 27, 2019	- -

Autosomal recessive nonsyndromic hearing loss 16 Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Apr 07, 2015	- -
Likely pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Feb 28, 2023	This variant occurred in homozygosity in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient was born to consanguineous parents and their family has no other history of hearing loss. This variant is a missense at a highly conserved site and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported to ClinVar with conflicting interpretations and is found in 331 heterozygotes and 5 homozygotes on gnomAD. Based on homozygosity, consistently predicted functional effect, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. -

STRC-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 15, 2024

The STRC c.4918C>T variant is predicted to result in the amino acid substitution p.Leu1640Phe. This variant has been reported in three patients with hearing loss in trans to a STRC full gene deletion, and was confirmed using an assay that excludes the STRCP1 pseudogene in two of these patients (Vona et al. 2015. PubMed ID: 26011646; described as c.4917_4918delinsCT, Mandelker et al. 2014. PubMed ID: 25157971; Table S2, Shearer et al. 2014. PubMed ID: 24963352). This variant is reported in 0.20% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including five homozygotes with unknown hearing status (http://gnomad.broadinstitute.org/variant/15-43892807-G-A). However, NGS based population database allele frequencies may not be accurate at this locus due to paralogy. Additionally, at PreventionGenetics and using an assay that excludes the STRCP1 pseudogene, we have observed this variant in the hemizygous state in trans to a STRC deletion in a patient with hearing loss as well as in the homozygous state in three patients undergoing testing unrelated to hearing loss. This variant is listed in ClinVar with conflicting interpretations of uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/417924/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.61	T;T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.088	T;T
MetaSVM	Uncertain	-0.091	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.079	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.95	P;P
Vest4		0.30
MVP		0.77
ClinPred		0.068	T
GERP RS		4.8
Varity_R		0.069
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2920791; hg19: chr15-43892807; COSMIC: COSV55853281; COSMIC: COSV55853281;