15-43600682-G-C

Variant names:

• chr15-43600682-G-C
• rs184909019
• NM_153700.2:c.4845C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_153700.2(STRC):​c.4845C>G​(p.Ser1615Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S1615S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: STRC NM_153700.2 missense, splice_region
• Scores: Splicing: ADA: 0.003945
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

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.4845C>G	p.Ser1615Arg	missense splice_region	Exon 26 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.4845C>G	p.Ser1615Arg	missense splice_region	Exon 26 of 29	ENSP00000401513.2
	STRC	ENST00000440125.5	TSL:1	n.*2637C>G		splice_region non_coding_transcript_exon	Exon 25 of 28	ENSP00000394866.1
	STRC	ENST00000440125.5	TSL:1	n.*2637C>G		3_prime_UTR	Exon 25 of 28	ENSP00000394866.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461434 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727020

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111748

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.063
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.30	T
PhyloP100		1.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.50
Sift	Benign	0.22	T
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.55		Gain of catalytic residue at S1615 (P = 0.0103)
MVP		0.76
ClinPred		0.65	D
GERP RS		1.8
Varity_R		0.078
gMVP		0.53
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0039
dbscSNV1_RF	Benign	0.15
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: rs184909019; hg19: chr15-43892880;