rs56385906

Variant names:

• chr15-43610931-A-G
• rs56385906
• NM_153700.2:c.3360T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_153700.2(STRC):​c.3360T>C​(p.Cys1120Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 146,078 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (86 hom., cov: 22)
  • Exomes 𝑓: 0.011 (2718 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.191
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-43610931-A-G is Benign according to our data. Variant chr15-43610931-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.191 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 86 AR gene

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.3360T>C	p.Cys1120Cys	synonymous	Exon 14 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.3360T>C	p.Cys1120Cys	synonymous	Exon 14 of 29	ENSP00000401513.2	Q7RTU9
	STRC	ENST00000440125.5	TSL:1	n.*1216-545T>C		intron	N/A	ENSP00000394866.1	E7EPM8
	STRC	ENST00000541030.5	TSL:5	c.1105-545T>C		intron	N/A	ENSP00000440413.1	F5GXA4

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2787 AN: 145958 Hom.: 86 Cov.: 22

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.0215

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0183

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.0310

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0133 AC: 3179 AN: 238230 AF XY: 0.0132

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.000382

Gnomad FIN exome AF: 0.00754

Gnomad NFE exome AF: 0.0186

Gnomad OTH exome AF: 0.0193

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0111 AC: 15335 AN: 1381298 Hom.: 2718 Cov.: 29 AF XY: 0.0112 AC XY: 7682 AN XY: 688280

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

African (AFR) AF: 0.000906 AC: 30 AN: 33116

American (AMR) AF: 0.00891 AC: 385 AN: 43234

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 297 AN: 25094

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39624

South Asian (SAS) AF: 0.00681 AC: 568 AN: 83386

European-Finnish (FIN) AF: 0.0141 AC: 728 AN: 51476

Middle Eastern (MID) AF: 0.00711 AC: 39 AN: 5488

European-Non Finnish (NFE) AF: 0.0121 AC: 12572 AN: 1042644

Other (OTH) AF: 0.0124 AC: 708 AN: 57236

⚠️ 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 AF: 0.0191 AC: 2784 AN: 146078 Hom.: 86 Cov.: 22 AF XY: 0.0185 AC XY: 1325 AN XY: 71594

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

African (AFR) AF: 0.00379 AC: 154 AN: 40668

American (AMR) AF: 0.0204 AC: 296 AN: 14540

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 60 AN: 3286

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.0114 AC: 53 AN: 4658

European-Finnish (FIN) AF: 0.0162 AC: 166 AN: 10260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0310 AC: 1996 AN: 64330

Other (OTH) AF: 0.0199 AC: 40 AN: 2012

⚠️ 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: 0.0387 Hom.: 52

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.8
DANN	Benign	0.84
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs56385906; hg19: chr15-43903129; COSMIC: COSV70833292; COSMIC: COSV70833292;