15-43614194-ACCTGCAGCTTCC-ACCTGCAGCTTCCCCTGCAGCTTCC

Variant names:

• chr15-43614194-A-ACCTGCAGCTTCC
• rs1021413948
• NM_153700.2:c.2303_2313+1dupGGAAGCTGCAGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_153700.2(STRC):​c.2303_2313+1dupGGAAGCTGCAGG variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 2)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: STRC NM_153700.2 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550
• 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]

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

ENSG00000309475 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02195946 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.6, offset of 12, new splice context is: cagGTgagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2	c.2303_2313+1dupGGAAGCTGCAGG		splice_donor_variant, intron_variant	Intron 6 of 28	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.2313+1_2313+2insGGAAGCTGCAGG		splice_donor_variant, intron_variant	Intron 6 of 28	5	NM_153700.2	ENSP00000401513.2
ENSG00000284772	ENST00000643290.1	n.*1535_*1536insGGAAGCTGCAGG		downstream_gene_variant				ENSP00000495476.1

Frequencies

GnomAD3 genomes Cov.: 2

GnomAD4 exome AF: 0.00000378 AC: 1 AN: 264398 Hom.: 0 Cov.: 0 AF XY: 0.00000716 AC XY: 1 AN XY: 139636

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

African (AFR) AF: 0.00 AC: 0 AN: 4388

American (AMR) AF: 0.00 AC: 0 AN: 12792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6368

East Asian (EAS) AF: 0.00 AC: 0 AN: 15994

South Asian (SAS) AF: 0.00 AC: 0 AN: 35340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16344

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

European-Non Finnish (NFE) AF: 0.00000633 AC: 1 AN: 158070

Other (OTH) AF: 0.00 AC: 0 AN: 14262

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.055

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1021413948; hg19: chr15-43906392;