11-17520892-T-C

Variant names:

• chr11-17520892-T-C
• rs2240487
• NM_153676.4:c.1188A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153676.4(USH1C):​c.1188A>G​(p.Pro396Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,613,522 control chromosomes in the GnomAD database, including 270,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21597 hom., cov: 32)
  • Exomes 𝑓: 0.58 (248931 hom.)
• Consequence: USH1C NM_153676.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.07
• Publications: 27 publications found

Genes affected

USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

USH1C Gene-Disease associations (from GenCC):

• Usher syndrome type 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-17520892-T-C is Benign according to our data. Variant chr11-17520892-T-C is described in ClinVar as Benign. ClinVar VariationId is 47976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153676.4. 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
	USH1C	NM_153676.4	MANE Select	c.1188A>G	p.Pro396Pro	synonymous	Exon 14 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.1188A>G	p.Pro396Pro	synonymous	Exon 14 of 21	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.1221A>G	p.Pro407Pro	synonymous	Exon 14 of 22	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.1188A>G	p.Pro396Pro	synonymous	Exon 14 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1188A>G	p.Pro396Pro	synonymous	Exon 14 of 21	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1131A>G	p.Pro377Pro	synonymous	Exon 13 of 20	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79131 AN: 151920 Hom.: 21579 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.660

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.519

GnomAD2 exomes AF: 0.576 AC: 144888 AN: 251476 AF XY: 0.573

Gnomad AFR exome AF: 0.334

Gnomad AMR exome AF: 0.670

Gnomad ASJ exome AF: 0.586

Gnomad EAS exome AF: 0.661

Gnomad FIN exome AF: 0.567

Gnomad NFE exome AF: 0.583

Gnomad OTH exome AF: 0.580

GnomAD4 exome AF: 0.581 AC: 848790 AN: 1461484 Hom.: 248931 Cov.: 52 AF XY: 0.580 AC XY: 421370 AN XY: 727066

African (AFR) AF: 0.333 AC: 11140 AN: 33474

American (AMR) AF: 0.664 AC: 29680 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 15080 AN: 26132

East Asian (EAS) AF: 0.674 AC: 26766 AN: 39700

South Asian (SAS) AF: 0.523 AC: 45085 AN: 86250

European-Finnish (FIN) AF: 0.574 AC: 30632 AN: 53406

Middle Eastern (MID) AF: 0.501 AC: 2886 AN: 5760

European-Non Finnish (NFE) AF: 0.588 AC: 653137 AN: 1111656

Other (OTH) AF: 0.569 AC: 34384 AN: 60382

GnomAD4 genome AF: 0.521 AC: 79190 AN: 152038 Hom.: 21597 Cov.: 32 AF XY: 0.523 AC XY: 38875 AN XY: 74334

African (AFR) AF: 0.345 AC: 14302 AN: 41448

American (AMR) AF: 0.610 AC: 9323 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2018 AN: 3468

East Asian (EAS) AF: 0.660 AC: 3409 AN: 5162

South Asian (SAS) AF: 0.529 AC: 2546 AN: 4814

European-Finnish (FIN) AF: 0.557 AC: 5901 AN: 10600

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.587 AC: 39861 AN: 67960

Other (OTH) AF: 0.521 AC: 1100 AN: 2112

Alfa AF: 0.560 Hom.: 38040

Bravo AF: 0.516

Asia WGS AF: 0.580 AC: 2015 AN: 3478

EpiCase AF: 0.570

EpiControl AF: 0.564

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	3	Usher syndrome type 1C (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 18A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.98
DANN	Benign	0.43
PhyloP100		-2.1
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: rs2240487; hg19: chr11-17542439; COSMIC: COSV50014017; COSMIC: COSV50014017;