rs587783023

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_206933.4(USH2A):ā€‹c.2414G>Cā€‹(p.Gly805Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000471 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Synonymous variant affecting the same amino acid position (i.e. G805G) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.000049 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 3.70
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a disulfide_bond (size 18) in uniprot entity USH2A_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_206933.4
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
USH2ANM_206933.4 linkuse as main transcriptc.2414G>C p.Gly805Ala missense_variant 13/72 ENST00000307340.8
USH2ANM_007123.6 linkuse as main transcriptc.2414G>C p.Gly805Ala missense_variant 13/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.2414G>C p.Gly805Ala missense_variant 13/721 NM_206933.4 P1O75445-1
USH2AENST00000366942.3 linkuse as main transcriptc.2414G>C p.Gly805Ala missense_variant 13/211 O75445-2
USH2AENST00000674083.1 linkuse as main transcriptc.2414G>C p.Gly805Ala missense_variant 13/73 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152098
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000772
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000917
AC:
23
AN:
250734
Hom.:
0
AF XY:
0.0000959
AC XY:
13
AN XY:
135496
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00125
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000493
AC:
72
AN:
1461782
Hom.:
0
Cov.:
31
AF XY:
0.0000468
AC XY:
34
AN XY:
727188
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00171
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152098
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000772
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.0000741
AC:
9
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCounsylFeb 09, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Usher syndrome type 2A Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabNov 04, 2023- -
Leber congenital amaurosis Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingMolecular Diagnostics Laboratory, Seoul National University HospitalSep 18, 2014- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 27, 2022This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 805 of the USH2A protein (p.Gly805Ala). This variant is present in population databases (rs587783023, gnomAD 0.1%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 25445212, 27057829, 33691693). ClinVar contains an entry for this variant (Variation ID: 156393). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabNov 04, 2023- -
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterresearchDept Of Ophthalmology, Nagoya UniversityOct 01, 2023- -
Retinitis pigmentosa Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.080
T
BayesDel_noAF
Uncertain
0.070
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
T;.
Eigen
Uncertain
0.68
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.71
T;T
M_CAP
Benign
0.025
T
MetaRNN
Uncertain
0.51
D;D
MetaSVM
Benign
-0.32
T
MutationAssessor
Uncertain
2.5
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-4.1
D;D
REVEL
Uncertain
0.36
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.016
D;T
Polyphen
1.0
D;D
Vest4
0.74
MutPred
0.49
Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP
0.96
MPC
0.24
ClinPred
0.43
T
GERP RS
5.7
Varity_R
0.58
gMVP
0.77

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.

Other links and lift over

dbSNP: rs587783023; hg19: chr1-216420322; COSMIC: COSV56422237; API