NM_206933.4:c.11946G>A

Variant names:

• chr1-215728150-C-T
• rs2820718
• NM_206933.4:c.11946G>A

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.11946G>A​(p.Leu3982Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,613,994 control chromosomes in the GnomAD database, including 26,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2291 hom., cov: 32)
  • Exomes 𝑓: 0.18 (23734 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.729
• Publications: 15 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=-0.35).
• BP6: Variant 1-215728150-C-T is Benign according to our data. Variant chr1-215728150-C-T is described in ClinVar as Benign. ClinVar VariationId is 48387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.729 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.183 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.11946G>A	p.Leu3982Leu	synonymous	Exon 61 of 72	NP_996816.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.11946G>A	p.Leu3982Leu	synonymous	Exon 61 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.11946G>A	p.Leu3982Leu	synonymous	Exon 61 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25590 AN: 151994 Hom.: 2287 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.173

GnomAD2 exomes AF: 0.154 AC: 38659 AN: 251332 AF XY: 0.157

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.0795

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.176 AC: 257422 AN: 1461884 Hom.: 23734 Cov.: 34 AF XY: 0.176 AC XY: 128025 AN XY: 727240

African (AFR) AF: 0.176 AC: 5876 AN: 33480

American (AMR) AF: 0.0829 AC: 3706 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 4974 AN: 26136

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39700

South Asian (SAS) AF: 0.147 AC: 12719 AN: 86258

European-Finnish (FIN) AF: 0.224 AC: 11969 AN: 53418

Middle Eastern (MID) AF: 0.189 AC: 1091 AN: 5768

European-Non Finnish (NFE) AF: 0.186 AC: 206504 AN: 1112004

Other (OTH) AF: 0.175 AC: 10557 AN: 60396

GnomAD4 genome AF: 0.168 AC: 25606 AN: 152110 Hom.: 2291 Cov.: 32 AF XY: 0.168 AC XY: 12467 AN XY: 74352

African (AFR) AF: 0.169 AC: 7004 AN: 41478

American (AMR) AF: 0.112 AC: 1717 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 680 AN: 3468

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5166

South Asian (SAS) AF: 0.136 AC: 655 AN: 4826

European-Finnish (FIN) AF: 0.219 AC: 2314 AN: 10570

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12622 AN: 68000

Other (OTH) AF: 0.173 AC: 366 AN: 2112

Alfa AF: 0.179 Hom.: 1277

Bravo AF: 0.160

Asia WGS AF: 0.0820 AC: 286 AN: 3478

EpiCase AF: 0.185

EpiControl AF: 0.187

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 13, 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.

PreventionGenetics, part of Exact Sciences

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

Nov 04, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Usher syndrome type 2A Benign:2

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

Retinal dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.3
DANN	Benign	0.85
PhyloP100		0.73
Mutation Taster		=100/0	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: rs2820718; hg19: chr1-215901492;