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
• Clinical Significance: Benign reviewed by expert panel P:1 U:4 B:6
• Conservation: PhyloP100: 7.68

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 -8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.7334C>T	p.Ser2445Phe	missense_variant	39/72	ENST00000307340.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152144 Hom.: 1 Cov.: 33

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.: 2 AF XY: 0.00111 AC XY: 150 AN XY: 135548

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.: 3 Cov.: 31 AF XY: 0.000517 AC XY: 376 AN XY: 727030

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: 34 AN: 152262 Hom.: 1 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74442

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: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

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

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	USH2A: BS1, BS2 -
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:1 Benign: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	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.47
MutPred		0.46		Loss of glycosylation at S2445 (P = 0.0094);
MVP		0.98
MPC		0.24
ClinPred		0.16	T
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

Other links and lift over

dbSNP: rs41315579; hg19: chr1-216074214;