rs41315579

Positions:

chr1-215900872-G-A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 197/30616) of the p.Ser2445Phe variant in the USH2A gene is 0.57% for South Asian chromosomes by gnomAD v2.1.1, 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/CA143592/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.00022 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 3 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:4B:6

Conservation

PhyloP100: 7.68

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.7334C>T	p.Ser2445Phe	missense_variant	39/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.7334C>T	p.Ser2445Phe	missense_variant	39/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
	ENST00000414995.1 linkuse as main transcript	n.208G>A		non_coding_transcript_exon_variant	2/2	3
USH2A	ENST00000674083.1 linkuse as main transcript	c.7334C>T	p.Ser2445Phe	missense_variant	39/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00684

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000841

AC:

211

AN:

250880

Hom.:

AF XY:

0.00111

AC XY:

150

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00643

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000357

AC:

522

AN:

1461440

Hom.:

Cov.:

AF XY:

0.000517

AC XY:

376

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00530

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000223

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00664

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.000898

AC:

109

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:4Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	USH2A: BS1, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The USH2A p.Ser2445Phe variant was identified in 1 of 1444 proband chromosomes (frequency: 0.00069) from individuals with inherited retinal disease (Carss_2017_PMID:28041643). The variant was identified in dbSNP (ID: rs41315579) and ClinVar (classified as uncertain significance by Laboratory for Molecular Medicine and Counsyl, and as likely pathogenic by NIHR Bioresource Rare Diseases, University of Cambridge). The variant was identified in control databases in 211 of 250880 chromosomes (2 homozygous) at a frequency of 0.000841 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 197 of 30616 chromosomes (freq: 0.006435), Other in 2 of 6114 chromosomes (freq: 0.000327), Latino in 3 of 34556 chromosomes (freq: 0.000087), European (non-Finnish) in 8 of 113262 chromosomes (freq: 0.000071) and East Asian in 1 of 18382 chromosomes (freq: 0.000054), but was not observed in the African, Ashkenazi Jewish, or European (Finnish) populations. Although the p.Ser2445 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2019	This variant is associated with the following publications: (PMID: 28041643) -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 05, 2022	- -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 14, 2011

Variant classified as Uncertain Significance - Favor Pathogenic. The Ser2445Phe variant in USH2A has been previously reported in dbSNP (rs41315579) without freq uency information (one heterozygous submission). The Ser2445 residue is conserve d in several mammals and distant species up to Zebrafish but is replaced by alan ine in mouse and rat. Biochemical and computational analyses (PolyPhen, SIFT and AlignGVGD) suggest that the variant may impact the protein. In addition, the id entification of this variant in this patient with a likely pathogenic variant in USH2A and a phenotype consistent with Usher type 2, increases the likelihood th at this variant is disease-causing. In summary, the clinical significance of thi s variant cannot be determined with certainty at this time; however based upon t he arguments described above, we would lean towards a more likely pathogenic rol e. -

Bardet-Biedl syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Jun 02, 2023

- -

Usher syndrome

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Mar 18, 2020

The filtering allele frequency (the lower threshold of the 95% CI of 197/30616) of the p.Ser2445Phe variant in the USH2A gene is 0.57% for South Asian chromosomes by gnomAD v2.1.1, 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). -

Usher syndrome type 2A

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.64

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

0.98

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.36

Sift

Uncertain

0.011

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.47

MutPred

0.46

Loss of glycosylation at S2445 (P = 0.0094);

MVP

0.98

MPC

0.24

ClinPred

0.16

GERP RS

6.0

Varity_R

0.24

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over