1-215741409-G-T

Variant names:

• chr1-215741409-G-T
• rs41303285
• NM_206933.4:c.11677C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_206933.4(USH2A):​c.11677C>A​(p.Pro3893Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0194 in 1,613,844 control chromosomes in the GnomAD database, including 396 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P3893P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 32)
  • Exomes 𝑓: 0.020 (377 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 6.11
• 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 -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.009347379).
• BP6: Variant 1-215741409-G-T is Benign according to our data. Variant chr1-215741409-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0128 (1952/152098) while in subpopulation NFE AF = 0.0195 (1325/67990). AF 95% confidence interval is 0.0186. There are 19 homozygotes in GnomAd4. There are 983 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.11677C>A	p.Pro3893Thr	missense	Exon 60 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.11677C>A	p.Pro3893Thr	missense	Exon 60 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.11677C>A	p.Pro3893Thr	missense	Exon 60 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1954 AN: 151982 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00336

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0127

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.00960

GnomAD2 exomes AF: 0.0158 AC: 3977 AN: 251428 AF XY: 0.0163

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0225

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0201 AC: 29380 AN: 1461746 Hom.: 377 Cov.: 31 AF XY: 0.0197 AC XY: 14347 AN XY: 727168

African (AFR) AF: 0.00266 AC: 89 AN: 33478

American (AMR) AF: 0.00360 AC: 161 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00306 AC: 80 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0152 AC: 1308 AN: 86252

European-Finnish (FIN) AF: 0.0319 AC: 1705 AN: 53404

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.0225 AC: 24998 AN: 1111930

Other (OTH) AF: 0.0167 AC: 1011 AN: 60386

GnomAD4 genome AF: 0.0128 AC: 1952 AN: 152098 Hom.: 19 Cov.: 32 AF XY: 0.0132 AC XY: 983 AN XY: 74336

African (AFR) AF: 0.00335 AC: 139 AN: 41520

American (AMR) AF: 0.00334 AC: 51 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4816

European-Finnish (FIN) AF: 0.0323 AC: 341 AN: 10548

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0195 AC: 1325 AN: 67990

Other (OTH) AF: 0.00950 AC: 20 AN: 2106

Alfa AF: 0.0174 Hom.: 97

Bravo AF: 0.0108

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0224 AC: 193

ExAC AF: 0.0173 AC: 2102

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0153

EpiControl AF: 0.0161

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Sep 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:5

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 10, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 21, 2017

Eurofins Ntd Llc (ga)

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

Jan 30, 2014

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:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 04, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinitis pigmentosa 39 Benign:1

Nov 04, 2023

Genome-Nilou Lab

Significance: Likely 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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.1
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.34
Sift	Benign	0.075	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.22
MPC		0.25
ClinPred		0.026	T
GERP RS		4.4
Varity_R		0.38
gMVP		0.63
Mutation Taster		=57/43	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: rs41303285; hg19: chr1-215914751; COSMIC: COSV99048391;