1-216246872-G-T

Position:

• chr1-216246872-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The p.Ser841Tyr variant in the USH2A gene has been identified in three individuals with Usher syndrome (PMIDs 19683999, 28944237, 28653555); however, in two of those individuals a variant on the second allele was not identified (PMIDs 19683999, 28944237) and in one (PMID 28653555), the variant found on the other alleles (p.Tyr1992Cys) did not have evidence to support pathogenicity and has a high allele frequency in gnomAD (of European (Finnish) chromosomes). The filtering allele frequency of the p.Ser841Tyr variant in the USH2A gene is 1.4% for European (Finnish) chromosomes by gnomAD (1144/128242 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA248655/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.0054 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (53 hom.)
• Consequence: USH2A ENST00000307340.8 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:4 B:16
• Conservation: PhyloP100: 3.95

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 -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.2522C>A	p.Ser841Tyr	missense_variant	13/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.2522C>A	p.Ser841Tyr	missense_variant	13/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.2522C>A	p.Ser841Tyr	missense_variant	13/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.2522C>A	p.Ser841Tyr	missense_variant	13/21	1		ENSP00000355909
USH2A	ENST00000674083.1	c.2522C>A	p.Ser841Tyr	missense_variant	13/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.00541 AC: 824 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00780

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00606 AC: 1517 AN: 250428 Hom.: 9 AF XY: 0.00608 AC XY: 822 AN XY: 135306

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.00912

Gnomad OTH exome AF: 0.00752

GnomAD4 exome AF: 0.00706 AC: 10316 AN: 1461822 Hom.: 53 Cov.: 31 AF XY: 0.00686 AC XY: 4990 AN XY: 727210

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00136

Gnomad4 FIN exome AF: 0.0140

Gnomad4 NFE exome AF: 0.00806

Gnomad4 OTH exome AF: 0.00578

GnomAD4 genome AF: 0.00542 AC: 825 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.00526 AC XY: 392 AN XY: 74484

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0139

Gnomad4 NFE AF: 0.00779

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00659 Hom.: 3

Bravo AF: 0.00471

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00628 AC: 763

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00622

EpiControl AF: 0.00705

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:4 Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 32581362, 32707200, 30872814, 30245029, 28944237, 28653555, 28041643, 25773295, 19683999, 22004887, 25262649) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	USH2A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 24, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Uncertain:1 Benign:5

Uncertain significance, flagged submission	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2022	Variant summary: USH2A c.2522C>A (p.Ser841Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0061 in 250428 control chromosomes, including 9 homozygotes. This frequency is not higher than the estimated maximum expected (MPAF) for a pathogenic variant in USH2A causing Usher Syndrome (0.011), however the presence of homozygotes suggests a benign role for the variant. In addition, the variant is reported in certain subpopulations with even higher frequencies, e.g. in the Finnish (0.016) and Swedish (0.015), which are above the MPAF, indicating that the variant is benign. Although the variant, c.2522C>A, has been reported to be found in individuals affected with Usher Syndrome related phenotypes (HGMD), the Deafness Variation Database (DVD), classified the variant as benign, based on ethnic-specific minor allele frequencies (Shearer_2014, Azaiez_2018). To our knowledge no experimental evidence demonstrating the variant impact on protein function have been reported. 12 submitters, including an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely pathogenic (n=1), VUS (n=4), likely benign (n=2) / benign (n=5; including the expert panel). 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	Jul 13, 2010	This variant is not expected to have clinical significance due to an equal occur rence in probands and controls (Pennings 2004). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Retinitis pigmentosa Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely pathogenic, flagged submission	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

Hearing impairment Uncertain:2

Uncertain significance, flagged submission	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Uncertain significance, flagged submission	research	Center for Statistical Genetics, Columbia University	Oct 08, 2018	- -

Usher syndrome type 2A Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Progressive cone dystrophy (without rod involvement) Uncertain:1

Uncertain significance, flagged submission

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Usher syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Dec 24, 2020

The p.Ser841Tyr variant in the USH2A gene has been identified in three individuals with Usher syndrome (PMIDs 19683999, 28944237, 28653555); however, in two of those individuals a variant on the second allele was not identified (PMIDs 19683999, 28944237) and in one (PMID 28653555), the variant found on the other alleles (p.Tyr1992Cys) did not have evidence to support pathogenicity and has a high allele frequency in gnomAD (of European (Finnish) chromosomes). The filtering allele frequency of the p.Ser841Tyr variant in the USH2A gene is 1.4% for European (Finnish) chromosomes by gnomAD (1144/128242 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0097	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.61
MVP		0.97
MPC		0.25
ClinPred		0.025	T
GERP RS		6.0
Varity_R		0.17
gMVP		0.75

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: rs111033282; hg19: chr1-216420214; COSMIC: COSV56354454;