1-216418592-T-C

Variant names:

• chr1-216418592-T-C
• rs73102592
• NM_206933.4:c.573A>G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_206933.4(USH2A):​c.573A>G​(p.Val191Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,613,368 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (79 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (88 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.31

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-216418592-T-C is Benign according to our data. Variant chr1-216418592-T-C is described in ClinVar as [Benign]. Clinvar id is 48540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216418592-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.573A>G	p.Val191Val	synonymous_variant	Exon 3 of 72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.573A>G	p.Val191Val	synonymous_variant	Exon 3 of 21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.573A>G	p.Val191Val	synonymous_variant	Exon 3 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.573A>G	p.Val191Val	synonymous_variant	Exon 3 of 21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.573A>G	p.Val191Val	synonymous_variant	Exon 3 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2937 AN: 152124 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.0626

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00610

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0380

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00749 AC: 1879 AN: 250906 Hom.: 26 AF XY: 0.00618 AC XY: 838 AN XY: 135610

Gnomad AFR exome AF: 0.0589

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.0355

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00309 AC: 4521 AN: 1461126 Hom.: 88 Cov.: 30 AF XY: 0.00289 AC XY: 2100 AN XY: 726838

Gnomad4 AFR exome AF: 0.0597

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.0336

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000331

Gnomad4 OTH exome AF: 0.00757

GnomAD4 genome AF: 0.0194 AC: 2952 AN: 152242 Hom.: 79 Cov.: 32 AF XY: 0.0185 AC XY: 1380 AN XY: 74428

Gnomad4 AFR AF: 0.0628

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0379

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.0113 Hom.: 19

Bravo AF: 0.0217

Asia WGS AF: 0.0250 AC: 89 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Usher syndrome type 2A Benign:3

Mar 20, 2019

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Nov 04, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Aug 17, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Val191Val in exon 3 of USH2A: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP (rs73102592 - no frequency data), and is rep orted as benign in one publication (Bernal 2005). -

Retinitis pigmentosa 39 Benign:1

Nov 04, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Retinitis pigmentosa Benign:1

Mar 20, 2019

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.0
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs73102592; hg19: chr1-216591934;