rs56385601

chr1-215888964-A-G

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.7685T>C(p.Val2562Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00756 in 1,614,060 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2562F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0059 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (58 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.93

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010328323).
• BP6: Variant 1-215888964-A-G is Benign according to our data. Variant chr1-215888964-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 48589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215888964-A-G is described in Lovd as [Likely_benign]. Variant chr1-215888964-A-G is described in Lovd as [Likely_pathogenic].
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.7685T>C	p.Val2562Ala	missense_variant	41/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.7685T>C	p.Val2562Ala	missense_variant	41/72	1	NM_206933.4	P1
	ENST00000414995.1	n.60+2323A>G		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.7685T>C	p.Val2562Ala	missense_variant	41/73

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 893 AN: 152094 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00867

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00649 AC: 1630 AN: 251140 Hom.: 15 AF XY: 0.00670 AC XY: 910 AN XY: 135732

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00466

Gnomad ASJ exome AF: 0.00984

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.00675

Gnomad NFE exome AF: 0.00950

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.00774 AC: 11317 AN: 1461848 Hom.: 58 Cov.: 32 AF XY: 0.00788 AC XY: 5733 AN XY: 727230

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00490

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00262

Gnomad4 FIN exome AF: 0.00614

Gnomad4 NFE exome AF: 0.00879

Gnomad4 OTH exome AF: 0.00634

GnomAD4 genome AF: 0.00587 AC: 893 AN: 152212 Hom.: 4 Cov.: 32 AF XY: 0.00563 AC XY: 419 AN XY: 74418

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00614

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00480

Gnomad4 NFE AF: 0.00867

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00864 Hom.: 9

Bravo AF: 0.00593

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00860 AC: 74

ExAC AF: 0.00651 AC: 790

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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: 31266775, 19683999, 23484092, 18273898, 20052763, 22681893, 26927203, 22004887) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	USH2A: BP4, BS2 -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 17, 2011	Val2562Ala in exon 41 of USH2A: This variant has been reported in nine individua ls with a clinical diagnosis of Usher Syndrome types 1, 2 or 3 (Dreyer 2008, Jai jo 2009). However, several of these individuals already had other explanations f or their Usher syndrome (Jaijo 2009). In addition, this amino acid is not highly conserved acroos evolution, with the mouse and rat having an alanine at positio n 2562. In addition, this variant is listed in dbSNP (rs56385601 - no frequency data available) and has been identified in 6/278 (2.2%) probands tested by our l aboratory, none of whom had a variant on their second USH2A allele. In summary, this variant meets our criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2022	Variant summary: USH2A c.7685T>C (p.Val2562Ala) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 251140 control chromosomes, predominantly at a frequency of 0.0095 within the Non-Finnish European subpopulation in the gnomAD database, including 12 homozygotes. This frequency is close to that estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0065 vs 0.011), supporting a neutral outcome. Although reported frequently in the literature, to our knowledge, no occurrence of c.7685T>C in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one report listed this variant along with two other pathogenic alleles in an individual with Usher syndrome, supporting a benign outcome (example, Hagag_2020). Five 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. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2019	- -

Usher syndrome type 2A Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 23, 2019	- -

Retinitis pigmentosa 39 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	16
Dann	Benign	0.91
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.10
Sift	Benign	0.79	T
Sift4G	Benign	0.21	T
Polyphen		0.0040	B
Vest4		0.71
MVP		0.84
MPC		0.037
ClinPred		0.0040	T
GERP RS		3.5
Varity_R		0.058
gMVP		0.25

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: rs56385601; hg19: chr1-216062306; COSMIC: COSV105134880;