rs876657585

Positions:

• chr15-43617727-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_153700.2(STRC):​c.694A>G​(p.Lys232Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000078 (0 hom., cov: 15)
  • Exomes 𝑓: 0.000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059924692).
• BP6: Variant 15-43617727-T-C is Benign according to our data. Variant chr15-43617727-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227973.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRC	NM_153700.2	c.694A>G	p.Lys232Glu	missense_variant	2/29	ENST00000450892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRC	ENST00000450892.7	c.694A>G	p.Lys232Glu	missense_variant	2/29	5	NM_153700.2	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 128080 Hom.: 0 Cov.: 15 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000759

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000103 AC: 12 AN: 1169060 Hom.: 0 Cov.: 17 AF XY: 0.0000102 AC XY: 6 AN XY: 587074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000807

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000575

Gnomad4 OTH exome AF: 0.0000796

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000780 AC: 1 AN: 128186 Hom.: 0 Cov.: 15 AF XY: 0.0000162 AC XY: 1 AN XY: 61792

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000758

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 01, 2015

p.Lys232Glu in exon 2 of STRC: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, >20 mammals have a Glutamic acid (Glu) at this position. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.1
DANN	Benign	0.66
DEOGEN2	Benign	0.018	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.67	N;N
REVEL	Benign	0.16
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.12
MutPred		0.18		Loss of ubiquitination at K232 (P = 0.0067);.;
MVP		0.43
ClinPred		0.060	T
GERP RS		3.0
Varity_R		0.054
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657585; hg19: chr15-43909925;