rs56056328

Positions:

• chr1-215838100-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_206933.4(USH2A):​c.9262G>A​(p.Glu3088Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00726 in 1,612,766 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (53 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.19

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014042646).
• BP6: Variant 1-215838100-C-T is Benign according to our data. Variant chr1-215838100-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 48618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215838100-C-T is described in Lovd as [Likely_benign]. Variant chr1-215838100-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.9262G>A	p.Glu3088Lys	missense_variant	47/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.9262G>A	p.Glu3088Lys	missense_variant	47/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.9262G>A	p.Glu3088Lys	missense_variant	47/73

Frequencies

GnomAD3 genomes AF: 0.00597 AC: 908 AN: 152132 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00636

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00789

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00636 AC: 1599 AN: 251272 Hom.: 12 AF XY: 0.00667 AC XY: 906 AN XY: 135798

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.00903

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00304

Gnomad FIN exome AF: 0.00998

Gnomad NFE exome AF: 0.00836

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.00740 AC: 10803 AN: 1460516 Hom.: 53 Cov.: 30 AF XY: 0.00740 AC XY: 5377 AN XY: 726660

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00543

Gnomad4 ASJ exome AF: 0.00781

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00292

Gnomad4 FIN exome AF: 0.00903

Gnomad4 NFE exome AF: 0.00817

Gnomad4 OTH exome AF: 0.00749

GnomAD4 genome AF: 0.00596 AC: 907 AN: 152250 Hom.: 3 Cov.: 32 AF XY: 0.00610 AC XY: 454 AN XY: 74436

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00636

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0133

Gnomad4 NFE AF: 0.00789

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00739 Hom.: 7

Bravo AF: 0.00552

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00637 AC: 773

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00949

EpiControl AF: 0.00913

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: USH2A c.9262G>A (p.Glu3088Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0064 in 251272 control chromosomes in the gnomAD database, including 12 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0064 vs 0.011), allowing no conclusion about variant significance. Although this variant has been reported in the literature, to our knowledge, no occurrence of c.9262G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 26, 2012	Glu3088Lys in exon 47 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (47/7020) of European American chromosomes and 0.2% (7/3738) of African American chromosomes from a broad popu lation by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; (rs56056328). It addition, it occurrs at an equal frequency in cases and contro ls (McGee 2010; Dreyer 2008). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2015	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 21909055, 20507924, 26927203, 18273898, 22004887, 21559123, 19683999, 25999674) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	USH2A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Usher syndrome type 2A Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.28
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.82
MVP		0.94
MPC		0.046
ClinPred		0.022	T
GERP RS		4.1
Varity_R		0.32
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56056328; hg19: chr1-216011442; COSMIC: COSV56426396;