rs56042996

Variant names:

• chr15-43605301-T-C
• rs2920780
• NM_153700.2:c.3893A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153700.2(STRC):​c.3893A>G​(p.His1298Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,590,212 control chromosomes in the GnomAD database, including 21,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5826 hom., cov: 30)
  • Exomes 𝑓: 0.12 (15712 hom.)
• Consequence: STRC NM_153700.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.35
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021159947).
• BP6: Variant 15-43605301-T-C is Benign according to our data. Variant chr15-43605301-T-C is described in ClinVar as Benign. ClinVar VariationId is 165312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRC	NM_153700.2	MANE Select	c.3893A>G	p.His1298Arg	missense	Exon 19 of 29	NP_714544.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRC	ENST00000450892.7	TSL:5 MANE Select	c.3893A>G	p.His1298Arg	missense	Exon 19 of 29	ENSP00000401513.2
	STRC	ENST00000440125.5	TSL:1	n.*1685A>G		non_coding_transcript_exon	Exon 18 of 28	ENSP00000394866.1
	STRC	ENST00000440125.5	TSL:1	n.*1685A>G		3_prime_UTR	Exon 18 of 28	ENSP00000394866.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32808 AN: 151178 Hom.: 5814 Cov.: 30

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.0402

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.0941

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.161 AC: 32392 AN: 200968 AF XY: 0.154

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.286

Gnomad FIN exome AF: 0.0391

Gnomad NFE exome AF: 0.0978

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.120 AC: 172233 AN: 1438918 Hom.: 15712 Cov.: 33 AF XY: 0.120 AC XY: 85682 AN XY: 713602

African (AFR) AF: 0.501 AC: 16632 AN: 33182

American (AMR) AF: 0.199 AC: 8160 AN: 40984

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 4817 AN: 25652

East Asian (EAS) AF: 0.274 AC: 10711 AN: 39088

South Asian (SAS) AF: 0.175 AC: 14580 AN: 83200

European-Finnish (FIN) AF: 0.0401 AC: 2084 AN: 51980

Middle Eastern (MID) AF: 0.134 AC: 760 AN: 5686

European-Non Finnish (NFE) AF: 0.0963 AC: 105933 AN: 1099614

Other (OTH) AF: 0.144 AC: 8556 AN: 59532

GnomAD4 genome AF: 0.217 AC: 32866 AN: 151294 Hom.: 5826 Cov.: 30 AF XY: 0.214 AC XY: 15799 AN XY: 73916

African (AFR) AF: 0.477 AC: 19613 AN: 41086

American (AMR) AF: 0.195 AC: 2960 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 628 AN: 3458

East Asian (EAS) AF: 0.273 AC: 1394 AN: 5108

South Asian (SAS) AF: 0.192 AC: 912 AN: 4760

European-Finnish (FIN) AF: 0.0402 AC: 424 AN: 10542

Middle Eastern (MID) AF: 0.175 AC: 51 AN: 292

European-Non Finnish (NFE) AF: 0.0940 AC: 6380 AN: 67844

Other (OTH) AF: 0.194 AC: 407 AN: 2094

Alfa AF: 0.171 Hom.: 719

Bravo AF: 0.245

ESP6500AA AF: 0.451 AC: 1981

ESP6500EA AF: 0.0978 AC: 836

ExAC AF: 0.147 AC: 17652

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Autosomal recessive nonsyndromic hearing loss 16 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.93	T
PhyloP100		1.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.098
Sift	Benign	0.22	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.13
ClinPred		0.0040	T
GERP RS		2.9
Varity_R		0.054
gMVP		0.39
Mutation Taster		=98/2	polymorphism (auto)

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: rs2920780; hg19: chr15-43897499; COSMIC: COSV68461473; COSMIC: COSV68461473;