rs876657585

Variant names:

• chr15-43617727-T-C
• rs876657585
• NM_153700.2:c.694A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

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. 15/21 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.05
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284772 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 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 VariationId is 227973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.694A>G	p.Lys232Glu	missense	Exon 2 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.694A>G	p.Lys232Glu	missense	Exon 2 of 29	ENSP00000401513.2	Q7RTU9
	STRC	ENST00000440125.5	TSL:1	n.694A>G		non_coding_transcript_exon	Exon 2 of 28	ENSP00000394866.1	E7EPM8
	ENSG00000284772	ENST00000643290.1		n.*857A>G		non_coding_transcript_exon	Exon 4 of 9	ENSP00000495476.1	A0A2R8Y6Q2

Frequencies

GnomAD3 genomes AF: 0.00000781 AC: 1 AN: 128080 Hom.: 0 Cov.: 15

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

⚠️ 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: 25776

American (AMR) AF: 0.0000807 AC: 3 AN: 37160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23812

East Asian (EAS) AF: 0.00 AC: 0 AN: 36388

South Asian (SAS) AF: 0.00 AC: 0 AN: 76838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3606

European-Non Finnish (NFE) AF: 0.00000575 AC: 5 AN: 870146

Other (OTH) AF: 0.0000796 AC: 4 AN: 50250

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000222939), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ 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: 30760

American (AMR) AF: 0.0000758 AC: 1 AN: 13190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3256

East Asian (EAS) AF: 0.00 AC: 0 AN: 4126

South Asian (SAS) AF: 0.00 AC: 0 AN: 3230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 61498

Other (OTH) AF: 0.00 AC: 0 AN: 1694

⚠️ 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: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.97	T
PhyloP100		1.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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

Other links and lift over

dbSNP: rs876657585; hg19: chr15-43909925;