rs876658007

Variant names:

• chr15-43613218-G-A
• rs876658007
• NM_153700.2:c.2494C>T

Variant summary

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

The NM_153700.2(STRC):​c.2494C>T​(p.Arg832Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. R832Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 6)
  • Exomes 𝑓: 0.000045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.42
• Publications: 1 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]

STRC Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 16

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000309475 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.2494C>T	p.Arg832Trp	missense	Exon 8 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.2494C>T	p.Arg832Trp	missense	Exon 8 of 29	ENSP00000401513.2	Q7RTU9
	STRC	ENST00000440125.5	TSL:1	n.*571C>T		non_coding_transcript_exon	Exon 9 of 28	ENSP00000394866.1	E7EPM8
	STRC	ENST00000440125.5	TSL:1	n.*571C>T		3_prime_UTR	Exon 9 of 28	ENSP00000394866.1	E7EPM8

Frequencies

GnomAD3 genomes AF: 0.0000421 AC: 2 AN: 47476 Hom.: 0 Cov.: 6

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000209

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: 0.0000355

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000403 AC: 2 AN: 49592 AF XY: 0.0000398

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000988

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: 0.000574

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000449 AC: 12 AN: 267192 Hom.: 0 Cov.: 4 AF XY: 0.0000413 AC XY: 6 AN XY: 145166

African (AFR) AF: 0.00 AC: 0 AN: 5446

American (AMR) AF: 0.000267 AC: 4 AN: 14972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6028

East Asian (EAS) AF: 0.00 AC: 0 AN: 12376

South Asian (SAS) AF: 0.00 AC: 0 AN: 43558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 840

European-Non Finnish (NFE) AF: 0.0000375 AC: 6 AN: 159964

Other (OTH) AF: 0.000160 AC: 2 AN: 12536

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000421 AC: 2 AN: 47476 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 22156

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4994

American (AMR) AF: 0.000209 AC: 1 AN: 4786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1354

East Asian (EAS) AF: 0.00 AC: 0 AN: 1906

South Asian (SAS) AF: 0.00 AC: 0 AN: 1236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 166

European-Non Finnish (NFE) AF: 0.0000355 AC: 1 AN: 28172

Other (OTH) AF: 0.00 AC: 0 AN: 596

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	-0.17	T
PhyloP100		2.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.59		Loss of disorder (P = 0.0093)
MVP		0.87
ClinPred		0.40	T
GERP RS		1.8
Varity_R		0.23
gMVP		0.71
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs876658007; hg19: chr15-43905416;