rs2915791

Variant names:

• chr15-43600624-C-A
• rs2915791
• NM_153700.2:c.4903G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-43600624-C-A
• chr15-43600624-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_153700.2(STRC):​c.4903G>T​(p.Val1635Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,446,766 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1635A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.21
• Publications: 6 publications found

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11853805).
• BP6: Variant 15-43600624-C-A is Benign according to our data. Variant chr15-43600624-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227972.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153700.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRC	NM_153700.2	MANE Select	c.4903G>T	p.Val1635Phe	missense	Exon 26 of 29	NP_714544.1	Q7RTU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRC	ENST00000450892.7	TSL:5 MANE Select	c.4903G>T	p.Val1635Phe	missense	Exon 26 of 29	ENSP00000401513.2	Q7RTU9
	STRC	ENST00000440125.5	TSL:1	n.*2695G>T		non_coding_transcript_exon	Exon 25 of 28	ENSP00000394866.1	E7EPM8
	STRC	ENST00000440125.5	TSL:1	n.*2695G>T		3_prime_UTR	Exon 25 of 28	ENSP00000394866.1	E7EPM8

Frequencies

GnomAD3 genomes AF: 0.000793 AC: 120 AN: 151254 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000557

Gnomad AMI AF: 0.00225

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00531

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000962

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.0000480 AC: 12 AN: 249900 AF XY: 0.0000519

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000269 AC: 389 AN: 1446766 Hom.: 0 Cov.: 32 AF XY: 0.000300 AC XY: 216 AN XY: 719254

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000269 AC: 9 AN: 33416

American (AMR) AF: 0.0000448 AC: 2 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00115 AC: 96 AN: 83810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5712

European-Non Finnish (NFE) AF: 0.000235 AC: 259 AN: 1100124

Other (OTH) AF: 0.000300 AC: 18 AN: 59906

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000786 AC: 119 AN: 151374 Hom.: 0 Cov.: 26 AF XY: 0.000703 AC XY: 52 AN XY: 73996

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000556 AC: 23 AN: 41392

American (AMR) AF: 0.000197 AC: 3 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00510 AC: 24 AN: 4704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000962 AC: 65 AN: 67582

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000923 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00141 AC: 171

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	not specified (1)
-	1	-	STRC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.064	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.21	T
PhyloP100		1.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.58	N
REVEL	Uncertain	0.31
Sift	Benign	0.11	T
Sift4G	Uncertain	0.023	D
Polyphen		0.57	P
Vest4		0.52
MVP		0.75
ClinPred		0.28	T
GERP RS		3.8
Varity_R		0.12
gMVP		0.66
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2915791; hg19: chr15-43892822; COSMIC: COSV55853538; COSMIC: COSV55853538;