rs41277210

chr1-215970707-C-T

Variant summary

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

The NM_206933.4(USH2A):c.6875G>A(p.Arg2292His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,613,568 control chromosomes in the GnomAD database, including 781 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2292C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (48 hom., cov: 32)
  • Exomes 𝑓: 0.028 (733 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.0800

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a domain Fibronectin type-III 9 (size 87) in uniprot entity USH2A_HUMAN there are 41 pathogenic changes around while only 8 benign (84%) in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.002261877).
• BP6: Variant 1-215970707-C-T is Benign according to our data. Variant chr1-215970707-C-T is described in ClinVar as [Benign]. Clinvar id is 48571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215970707-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0195 (2972/152152) while in subpopulation NFE AF= 0.0288 (1956/67996). AF 95% confidence interval is 0.0277. There are 48 homozygotes in gnomad4. There are 1454 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.6875G>A	p.Arg2292His	missense_variant	36/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.6875G>A	p.Arg2292His	missense_variant	36/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.6875G>A	p.Arg2292His	missense_variant	36/73

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2972 AN: 152034 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.00507

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.00820

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0433

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0288

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0214 AC: 5374 AN: 251062 Hom.: 99 AF XY: 0.0222 AC XY: 3008 AN XY: 135676

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.00606

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0149

Gnomad FIN exome AF: 0.0442

Gnomad NFE exome AF: 0.0303

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0276 AC: 40391 AN: 1461416 Hom.: 733 Cov.: 32 AF XY: 0.0271 AC XY: 19675 AN XY: 727002

Gnomad4 AFR exome AF: 0.00383

Gnomad4 AMR exome AF: 0.00654

Gnomad4 ASJ exome AF: 0.00976

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0159

Gnomad4 FIN exome AF: 0.0441

Gnomad4 NFE exome AF: 0.0311

Gnomad4 OTH exome AF: 0.0235

GnomAD4 genome AF: 0.0195 AC: 2972 AN: 152152 Hom.: 48 Cov.: 32 AF XY: 0.0195 AC XY: 1454 AN XY: 74374

Gnomad4 AFR AF: 0.00506

Gnomad4 AMR AF: 0.00818

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.0433

Gnomad4 NFE AF: 0.0288

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0263 Hom.: 58

Bravo AF: 0.0167

TwinsUK AF: 0.0280 AC: 104

ALSPAC AF: 0.0353 AC: 136

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0303 AC: 261

ExAC AF: 0.0224 AC: 2719

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0256

EpiControl AF: 0.0240

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 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. -

Usher syndrome type 2A Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

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
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.90
Dann	Benign	0.86
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.056
Sift	Benign	0.61	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.044
MPC		0.034
ClinPred		0.0022	T
GERP RS		0.79
Varity_R		0.027
gMVP		0.26

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: rs41277210; hg19: chr1-216144049; COSMIC: COSV56448114;