rs111033412

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_206933.4(USH2A):c.6721C>T(p.Pro2241Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2241L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 8.04

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-215993103-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 560523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

PP5

Variant 1-215993104-G-A is Pathogenic according to our data. Variant chr1-215993104-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48569.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.6721C>T	p.Pro2241Ser	missense_variant	Exon 35 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.6721C>T	p.Pro2241Ser	missense_variant	Exon 35 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.6721C>T	p.Pro2241Ser	missense_variant	Exon 35 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Sep 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2241 of the USH2A protein (p.Pro2241Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (internal data). ClinVar contains an entry for this variant (Variation ID: 48569). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. This variant disrupts the p.Pro2241 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25999674, 26927203, 27318125, 28224992; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:1

Apr 10, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Pro2241Ser variant in USH2A has not been reported in the literature nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, conservation, PolyPhen2, SIFT, AlignGVGD) suggest that the varia nt may impact the protein. However, this information is not predictive enough to determine pathogenicity. It should also be noted that this variant was identifi ed in cis with the Cys759Phe USH2A variant. In summary, the clinical significanc e of this variant cannot be determined with certainty at this time. -

Usher syndrome type 2A

Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.22

MutationAssessor

Pathogenic

3.4

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.81

MutPred

0.44

Gain of glycosylation at P2241 (P = 0.0103);

MVP

0.95

MPC

0.24

ClinPred

1.0

GERP RS

6.2

Varity_R

0.48

gMVP

0.84

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

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