1-216323590-C-G

Variant names:

• chr1-216323590-C-G
• rs35730265
• NM_206933.4:c.1434G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_206933.4(USH2A):​c.1434G>C​(p.Glu478Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,613,512 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E478E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 31)
  • Exomes 𝑓: 0.016 (235 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 0.0430
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 39

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007865071).
• BP6: Variant 1-216323590-C-G is Benign according to our data. Variant chr1-216323590-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48437.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1920/152048) while in subpopulation NFE AF = 0.0187 (1270/67972). AF 95% confidence interval is 0.0178. There are 18 homozygotes in GnomAd4. There are 921 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206933.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.1434G>C	p.Glu478Asp	missense	Exon 8 of 72	NP_996816.3
	USH2A	NM_007123.6		c.1434G>C	p.Glu478Asp	missense	Exon 8 of 21	NP_009054.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.1434G>C	p.Glu478Asp	missense	Exon 8 of 72	ENSP00000305941.3
	USH2A	ENST00000366942.3	TSL:1	c.1434G>C	p.Glu478Asp	missense	Exon 8 of 21	ENSP00000355909.3
	USH2A	ENST00000674083.1		c.1434G>C	p.Glu478Asp	missense	Exon 8 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1920 AN: 151932 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.00353

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.0121 AC: 3034 AN: 250826 AF XY: 0.0119

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00811

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0165 AC: 24111 AN: 1461464 Hom.: 235 Cov.: 30 AF XY: 0.0163 AC XY: 11829 AN XY: 727034

African (AFR) AF: 0.00293 AC: 98 AN: 33454

American (AMR) AF: 0.00882 AC: 394 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 479 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00243 AC: 210 AN: 86250

European-Finnish (FIN) AF: 0.0165 AC: 883 AN: 53418

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5760

European-Non Finnish (NFE) AF: 0.0190 AC: 21163 AN: 1111776

Other (OTH) AF: 0.0143 AC: 863 AN: 60370

GnomAD4 genome AF: 0.0126 AC: 1920 AN: 152048 Hom.: 18 Cov.: 31 AF XY: 0.0124 AC XY: 921 AN XY: 74270

African (AFR) AF: 0.00352 AC: 146 AN: 41508

American (AMR) AF: 0.0114 AC: 174 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 81 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.0151 AC: 159 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0187 AC: 1270 AN: 67972

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0174 Hom.: 21

Bravo AF: 0.0124

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0157 AC: 135

ExAC AF: 0.0118 AC: 1437

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0179

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Sep 22, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 17, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:4

May 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

USH2A: BP4, BS1, BS2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 20, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Usher syndrome type 2A Benign:3

Apr 27, 2017

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.

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal dystrophy Benign:2

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Jan 01, 2016

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinitis pigmentosa Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.043
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.044
Sift	Benign	0.15	T
Sift4G	Uncertain	0.037	D
Polyphen		0.10	B
Vest4		0.076
MutPred		0.65		Loss of ubiquitination at K481 (P = 0.1778)
MPC		0.12
ClinPred		0.016	T
GERP RS		0.84
Varity_R		0.13
gMVP		0.44
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs35730265; hg19: chr1-216496932; COSMIC: COSV99048308;