chr15-43600197-G-A

Variant names:

• chr15-43600197-G-A
• rs1397103328
• NM_153700.2:c.5090C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153700.2(STRC):​c.5090C>T​(p.Ala1697Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000864 in 1,273,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1697S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: STRC NM_153700.2 missense, splice_region
• Scores: Splicing: ADA: 0.001310
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33108425).

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.5090C>T	p.Ala1697Val	missense splice_region	Exon 27 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.5090C>T	p.Ala1697Val	missense splice_region	Exon 27 of 29	ENSP00000401513.2	Q7RTU9
	STRC	ENST00000440125.5	TSL:1	n.*2882C>T		splice_region non_coding_transcript_exon	Exon 26 of 28	ENSP00000394866.1	E7EPM8
	STRC	ENST00000440125.5	TSL:1	n.*2882C>T		3_prime_UTR	Exon 26 of 28	ENSP00000394866.1	E7EPM8

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000134 AC: 2 AN: 149220 AF XY: 0.0000251

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000864 AC: 11 AN: 1273816 Hom.: 0 Cov.: 18 AF XY: 0.0000110 AC XY: 7 AN XY: 636568

African (AFR) AF: 0.00 AC: 0 AN: 29800

American (AMR) AF: 0.00 AC: 0 AN: 37986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24388

East Asian (EAS) AF: 0.00 AC: 0 AN: 36868

South Asian (SAS) AF: 0.000129 AC: 10 AN: 77726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5402

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 957466

Other (OTH) AF: 0.0000185 AC: 1 AN: 53950

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.12	T
PhyloP100		1.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.025	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.22
MutPred		0.33		Gain of sheet (P = 0.0827)
MVP		0.65
ClinPred		0.59	D
GERP RS		3.0
Varity_R		0.066
gMVP		0.44
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.084
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

Other links and lift over

dbSNP: rs1397103328; hg19: chr15-43892395;