rs56110889

chr1-216084852-G-T

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.5013C>A(p.Gly1671=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,611,682 control chromosomes in the GnomAD database, including 23,188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2188 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21000 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.171

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]

USH2A-AS2 (HGNC:40605): (USH2A antisense RNA 2)

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 1-216084852-G-T is Benign according to our data. Variant chr1-216084852-G-T is described in ClinVar as [Benign]. Clinvar id is 48527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216084852-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.171 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.5013C>A	p.Gly1671=	synonymous_variant	25/72	ENST00000307340.8
USH2A-AS2	NR_125992.1	n.266-1870G>T		intron_variant, non_coding_transcript_variant
USH2A-AS2	NR_125993.1	n.137-1870G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.5013C>A	p.Gly1671=	synonymous_variant	25/72	1	NM_206933.4	P1
USH2A-AS2	ENST00000446411.5	n.266-1870G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24671 AN: 151924 Hom.: 2189 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0584

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.146

GnomAD3 exomes AF: 0.133 AC: 33426 AN: 250622 Hom.: 2689 AF XY: 0.133 AC XY: 18045 AN XY: 135452

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.0944

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0772

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.163 AC: 237752 AN: 1459640 Hom.: 21000 Cov.: 32 AF XY: 0.161 AC XY: 116997 AN XY: 726212

Gnomad4 AFR exome AF: 0.204

Gnomad4 AMR exome AF: 0.0967

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0788

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.180

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.162 AC: 24671 AN: 152042 Hom.: 2188 Cov.: 32 AF XY: 0.156 AC XY: 11608 AN XY: 74314

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0576

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.144

Alfa AF: 0.177 Hom.: 997

Bravo AF: 0.167

Asia WGS AF: 0.0440 AC: 155 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Usher syndrome type 2A Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	6.8
Dann	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs56110889; hg19: chr1-216258194; COSMIC: COSV56425186;