rs144817385

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_206933.4(USH2A):ā€‹c.6998T>Cā€‹(p.Val2333Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00026 ( 0 hom., cov: 32)
Exomes š‘“: 0.00014 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

2
5
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 7.32
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.021000445).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USH2ANM_206933.4 linkuse as main transcriptc.6998T>C p.Val2333Ala missense_variant 37/72 ENST00000307340.8 NP_996816.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.6998T>C p.Val2333Ala missense_variant 37/721 NM_206933.4 ENSP00000305941 P1O75445-1
USH2AENST00000674083.1 linkuse as main transcriptc.6998T>C p.Val2333Ala missense_variant 37/73 ENSP00000501296 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.000263
AC:
40
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00597
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000402
AC:
101
AN:
251046
Hom.:
0
AF XY:
0.000339
AC XY:
46
AN XY:
135690
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00473
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000140
AC:
205
AN:
1461480
Hom.:
0
Cov.:
31
AF XY:
0.000131
AC XY:
95
AN XY:
727046
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00320
Gnomad4 SAS exome
AF:
0.000186
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000306
Gnomad4 OTH exome
AF:
0.000398
GnomAD4 genome
AF:
0.000263
AC:
40
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.000255
AC XY:
19
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00599
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000256
Hom.:
0
Bravo
AF:
0.000280
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000329
AC:
40
Asia WGS
AF:
0.00577
AC:
20
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 05, 2021Identified with other USH2A variants in individuals with hearing loss and/or retinitis pigmentosa in published literature (Sun et al., 2018; Ng et al., 2019; Xu et al., 2014; Yuan Y et al., 2020); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31541171, 31054281, 29625443, 24938718, 30948794) -
Uncertain significance, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBlueprint GeneticsJun 12, 2018- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 30, 2017p.Val233Ala in exon 37 of USH2A: This variant is not expected to have clinical s ignificance because it has been identified in 0.46% (87/18850) of East Asian chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org/; dbSNP rs144817385). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.31
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.63
T
M_CAP
Pathogenic
0.54
D
MetaRNN
Benign
0.021
T
MetaSVM
Benign
-0.70
T
MutationAssessor
Uncertain
2.7
M
MutationTaster
Benign
0.99
D;D
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-2.3
N
REVEL
Benign
0.27
Sift
Benign
0.052
T
Sift4G
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
0.59
MVP
0.85
MPC
0.19
ClinPred
0.053
T
GERP RS
5.6
Varity_R
0.18
gMVP
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs144817385; hg19: chr1-216138781; API