rs138763871

Variant names:

• chr15-43601536-G-A
• rs138763871
• NM_153700.2:c.4561C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-43601536-G-A
• chr15-43601536-G-C
• chr15-43601536-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_153700.2(STRC):​c.4561C>T​(p.Arg1521Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,611,700 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1521Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (18 hom., cov: 29)
  • Exomes 𝑓: 0.0034 (97 hom.)
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.518
• Publications: 5 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073873997).
• BP6: Variant 15-43601536-G-A is Benign according to our data. Variant chr15-43601536-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 165306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRC	NM_153700.2	MANE Select	c.4561C>T	p.Arg1521Trp	missense	Exon 24 of 29	NP_714544.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRC	ENST00000450892.7	TSL:5 MANE Select	c.4561C>T	p.Arg1521Trp	missense	Exon 24 of 29	ENSP00000401513.2
	STRC	ENST00000440125.5	TSL:1	n.*2353C>T		non_coding_transcript_exon	Exon 23 of 28	ENSP00000394866.1
	STRC	ENST00000440125.5	TSL:1	n.*2353C>T		3_prime_UTR	Exon 23 of 28	ENSP00000394866.1

Frequencies

GnomAD3 genomes AF: 0.00504 AC: 766 AN: 151914 Hom.: 18 Cov.: 29

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0393

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00318

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00491 AC: 1234 AN: 251096 AF XY: 0.00488

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.00304

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00337 AC: 4919 AN: 1459668 Hom.: 97 Cov.: 32 AF XY: 0.00340 AC XY: 2467 AN XY: 726172

African (AFR) AF: 0.00320 AC: 107 AN: 33462

American (AMR) AF: 0.000738 AC: 33 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26104

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39674

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86202

European-Finnish (FIN) AF: 0.0358 AC: 1909 AN: 53372

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5762

European-Non Finnish (NFE) AF: 0.00237 AC: 2630 AN: 1110052

Other (OTH) AF: 0.00302 AC: 182 AN: 60330

GnomAD4 genome AF: 0.00503 AC: 765 AN: 152032 Hom.: 18 Cov.: 29 AF XY: 0.00654 AC XY: 486 AN XY: 74316

African (AFR) AF: 0.00268 AC: 111 AN: 41466

American (AMR) AF: 0.000721 AC: 11 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.0393 AC: 416 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00316 AC: 215 AN: 67946

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00253 Hom.: 2

Bravo AF: 0.00213

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00451 AC: 547

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00241

EpiControl AF: 0.00244

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.63	T
PhyloP100		0.52
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.52
MVP		0.84
ClinPred		0.020	T
GERP RS		0.40
Varity_R		0.095
gMVP		0.36
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs138763871; hg19: chr15-43893734; COSMIC: COSV55853401; COSMIC: COSV55853401;