rs74643365

Variant names:

• chr15-43601535-C-T
• rs74643365
• NM_153700.2:c.4562G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-43601535-C-T
• chr15-43601535-C-A
• chr15-43601535-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153700.2(STRC):​c.4562G>A​(p.Arg1521Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 1,613,514 control chromosomes in the GnomAD database, including 3,329 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1521W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.041 (225 hom., cov: 29)
  • Exomes 𝑓: 0.054 (3104 hom.)
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0120
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018331409).
• BP6: Variant 15-43601535-C-T is Benign according to our data. Variant chr15-43601535-C-T is described in ClinVar as Benign. ClinVar VariationId is 165304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

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.4562G>A	p.Arg1521Gln	missense	Exon 24 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.4562G>A	p.Arg1521Gln	missense	Exon 24 of 29	ENSP00000401513.2	Q7RTU9
	STRC	ENST00000440125.5	TSL:1	n.*2354G>A		non_coding_transcript_exon	Exon 23 of 28	ENSP00000394866.1	E7EPM8
	STRC	ENST00000440125.5	TSL:1	n.*2354G>A		3_prime_UTR	Exon 23 of 28	ENSP00000394866.1	E7EPM8

Frequencies

GnomAD3 genomes AF: 0.0412 AC: 6249 AN: 151832 Hom.: 225 Cov.: 29

Gnomad AFR AF: 0.00990

Gnomad AMI AF: 0.0751

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.0791

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0291

Gnomad FIN AF: 0.0758

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0583

Gnomad OTH AF: 0.0461

GnomAD2 exomes AF: 0.0459 AC: 11537 AN: 251130 AF XY: 0.0471

Gnomad AFR exome AF: 0.00964

Gnomad AMR exome AF: 0.0257

Gnomad ASJ exome AF: 0.0767

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.0704

Gnomad NFE exome AF: 0.0601

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0544 AC: 79437 AN: 1461564 Hom.: 3104 Cov.: 32 AF XY: 0.0540 AC XY: 39231 AN XY: 727100

African (AFR) AF: 0.00887 AC: 297 AN: 33478

American (AMR) AF: 0.0272 AC: 1214 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0750 AC: 1959 AN: 26128

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39692

South Asian (SAS) AF: 0.0371 AC: 3200 AN: 86244

European-Finnish (FIN) AF: 0.0653 AC: 3485 AN: 53386

Middle Eastern (MID) AF: 0.0940 AC: 542 AN: 5764

European-Non Finnish (NFE) AF: 0.0590 AC: 65639 AN: 1111780

Other (OTH) AF: 0.0510 AC: 3077 AN: 60378

GnomAD4 genome AF: 0.0411 AC: 6248 AN: 151950 Hom.: 225 Cov.: 29 AF XY: 0.0419 AC XY: 3108 AN XY: 74246

African (AFR) AF: 0.00987 AC: 409 AN: 41438

American (AMR) AF: 0.0301 AC: 459 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0791 AC: 274 AN: 3464

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5168

South Asian (SAS) AF: 0.0291 AC: 140 AN: 4814

European-Finnish (FIN) AF: 0.0758 AC: 800 AN: 10552

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0584 AC: 3965 AN: 67936

Other (OTH) AF: 0.0456 AC: 96 AN: 2106

Alfa AF: 0.0473 Hom.: 205

Bravo AF: 0.0365

TwinsUK AF: 0.0647 AC: 240

ALSPAC AF: 0.0576 AC: 222

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.0606 AC: 521

ExAC AF: 0.0465 AC: 5645

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.0593

EpiControl AF: 0.0577

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.012
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.063
Sift	Benign	0.31	T
Sift4G	Benign	0.57	T
Polyphen		0.0010	B
Vest4		0.20
ClinPred		0.0063	T
GERP RS		1.7
Varity_R		0.061
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74643365; hg19: chr15-43893733; COSMIC: COSV107359476; COSMIC: COSV107359476;