chr1-216323605-G-A

Variant names:

• chr1-216323605-G-A
• rs1805050
• NM_206933.4:c.1419C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_206933.4(USH2A):​c.1419C>T​(p.Thr473Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,613,018 control chromosomes in the GnomAD database, including 51,530 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T473T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (6189 hom., cov: 31)
  • Exomes 𝑓: 0.25 (45341 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.582
• Publications: 23 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-216323605-G-A is Benign according to our data. Variant chr1-216323605-G-A is described in ClinVar as Benign. ClinVar VariationId is 48431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.582 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

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.1419C>T	p.Thr473Thr	synonymous	Exon 8 of 72	NP_996816.3
	USH2A	NM_007123.6		c.1419C>T	p.Thr473Thr	synonymous	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.1419C>T	p.Thr473Thr	synonymous	Exon 8 of 72	ENSP00000305941.3
	USH2A	ENST00000366942.3	TSL:1	c.1419C>T	p.Thr473Thr	synonymous	Exon 8 of 21	ENSP00000355909.3
	USH2A	ENST00000674083.1		c.1419C>T	p.Thr473Thr	synonymous	Exon 8 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42091 AN: 151598 Hom.: 6167 Cov.: 31

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.287

GnomAD2 exomes AF: 0.250 AC: 62657 AN: 250742 AF XY: 0.250

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.266

Gnomad ASJ exome AF: 0.280

Gnomad EAS exome AF: 0.134

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.246 AC: 359394 AN: 1461302 Hom.: 45341 Cov.: 34 AF XY: 0.247 AC XY: 179765 AN XY: 726942

African (AFR) AF: 0.388 AC: 12969 AN: 33436

American (AMR) AF: 0.263 AC: 11761 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7315 AN: 26114

East Asian (EAS) AF: 0.129 AC: 5102 AN: 39622

South Asian (SAS) AF: 0.270 AC: 23296 AN: 86248

European-Finnish (FIN) AF: 0.187 AC: 9994 AN: 53418

Middle Eastern (MID) AF: 0.313 AC: 1804 AN: 5756

European-Non Finnish (NFE) AF: 0.245 AC: 271948 AN: 1111652

Other (OTH) AF: 0.252 AC: 15205 AN: 60366

GnomAD4 genome AF: 0.278 AC: 42142 AN: 151716 Hom.: 6189 Cov.: 31 AF XY: 0.274 AC XY: 20276 AN XY: 74092

African (AFR) AF: 0.380 AC: 15694 AN: 41328

American (AMR) AF: 0.264 AC: 4011 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 967 AN: 3468

East Asian (EAS) AF: 0.133 AC: 680 AN: 5132

South Asian (SAS) AF: 0.251 AC: 1207 AN: 4810

European-Finnish (FIN) AF: 0.176 AC: 1859 AN: 10544

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16874 AN: 67914

Other (OTH) AF: 0.285 AC: 598 AN: 2100

Alfa AF: 0.261 Hom.: 23461

Bravo AF: 0.289

Asia WGS AF: 0.203 AC: 707 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.265

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Apr 10, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 05, 2011

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.

Usher syndrome type 2A Benign:3

Jul 01, 2021

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.9
DANN	Benign	0.62
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1805050; hg19: chr1-216496947; COSMIC: COSV56343492;