rs2467437

Variant names:

• chr15-43608777-G-A
• rs2467437
• NM_153700.2:c.3557+499C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_153700.2(STRC):​c.3557+499C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 138,384 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0045 (4 hom., cov: 26)
• Consequence: STRC NM_153700.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.842
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2	c.3557+499C>T		intron_variant	Intron 16 of 28	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.3557+499C>T		intron_variant	Intron 16 of 28	5	NM_153700.2	ENSP00000401513.2

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 621 AN: 138316 Hom.: 4 Cov.: 26

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00825

Gnomad AMR AF: 0.00248

Gnomad ASJ AF: 0.00338

Gnomad EAS AF: 0.00523

Gnomad SAS AF: 0.00181

Gnomad FIN AF: 0.000199

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.000547

Gnomad OTH AF: 0.00523

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00452 AC: 625 AN: 138384 Hom.: 4 Cov.: 26 AF XY: 0.00461 AC XY: 310 AN XY: 67300

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

African (AFR) AF: 0.0146 AC: 492 AN: 33658

American (AMR) AF: 0.00255 AC: 35 AN: 13730

Ashkenazi Jewish (ASJ) AF: 0.00338 AC: 11 AN: 3252

East Asian (EAS) AF: 0.00525 AC: 23 AN: 4384

South Asian (SAS) AF: 0.00182 AC: 8 AN: 4402

European-Finnish (FIN) AF: 0.000199 AC: 2 AN: 10072

Middle Eastern (MID) AF: 0.00357 AC: 1 AN: 280

European-Non Finnish (NFE) AF: 0.000547 AC: 36 AN: 65830

Other (OTH) AF: 0.00519 AC: 10 AN: 1928

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0191 Hom.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.4
DANN	Benign	0.77
PhyloP100		0.84
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2467437; hg19: chr15-43900975; COSMIC: COSV68660367; COSMIC: COSV68660367;