rs17776775

Variant names:

• chr11-17509599-G-A
• rs17776775
• NM_153676.4:c.1770C>T

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.1770C>T​(p.Ala590Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.055 in 1,600,338 control chromosomes in the GnomAD database, including 3,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (212 hom., cov: 26)
  • Exomes 𝑓: 0.057 (3530 hom.)
• Consequence: USH1C NM_153676.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.752
• Publications: 6 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=-0.49).
• BP6: Variant 11-17509599-G-A is Benign according to our data. Variant chr11-17509599-G-A is described in ClinVar as Benign. ClinVar VariationId is 47982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.752 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.164 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.1770C>T	p.Ala590Ala	synonymous	Exon 18 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.1285-7619C>T		intron	N/A	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.1470+2303C>T		intron	N/A	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.1770C>T	p.Ala590Ala	synonymous	Exon 18 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1285-7619C>T		intron	N/A	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1228-7619C>T		intron	N/A	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 5954 AN: 150506 Hom.: 212 Cov.: 26

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0341

Gnomad EAS AF: 0.0347

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.0356

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0491

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0610 AC: 13848 AN: 227166 AF XY: 0.0687

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.0270

Gnomad ASJ exome AF: 0.0363

Gnomad EAS exome AF: 0.0268

Gnomad FIN exome AF: 0.0395

Gnomad NFE exome AF: 0.0521

Gnomad OTH exome AF: 0.0569

GnomAD4 exome AF: 0.0566 AC: 82057 AN: 1449716 Hom.: 3530 Cov.: 40 AF XY: 0.0605 AC XY: 43540 AN XY: 719888

African (AFR) AF: 0.0132 AC: 443 AN: 33434

American (AMR) AF: 0.0278 AC: 1216 AN: 43764

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 901 AN: 25818

East Asian (EAS) AF: 0.0359 AC: 1414 AN: 39354

South Asian (SAS) AF: 0.195 AC: 16539 AN: 84758

European-Finnish (FIN) AF: 0.0344 AC: 1697 AN: 49306

Middle Eastern (MID) AF: 0.0729 AC: 411 AN: 5636

European-Non Finnish (NFE) AF: 0.0505 AC: 55933 AN: 1107598

Other (OTH) AF: 0.0583 AC: 3503 AN: 60048

GnomAD4 genome AF: 0.0395 AC: 5948 AN: 150622 Hom.: 212 Cov.: 26 AF XY: 0.0406 AC XY: 2981 AN XY: 73470

African (AFR) AF: 0.0138 AC: 567 AN: 41102

American (AMR) AF: 0.0335 AC: 507 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.0341 AC: 118 AN: 3460

East Asian (EAS) AF: 0.0347 AC: 176 AN: 5066

South Asian (SAS) AF: 0.174 AC: 779 AN: 4474

European-Finnish (FIN) AF: 0.0356 AC: 374 AN: 10518

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0491 AC: 3316 AN: 67576

Other (OTH) AF: 0.0374 AC: 78 AN: 2086

Alfa AF: 0.0473 Hom.: 103

Bravo AF: 0.0369

Asia WGS AF: 0.0990 AC: 345 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.4
DANN	Benign	0.41
PhyloP100		0.75
Mutation Taster		=83/17	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: rs17776775; hg19: chr11-17531146; COSMIC: COSV50016008; COSMIC: COSV50016008;