rs146805130

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_206933.4(USH2A):ā€‹c.1623G>Cā€‹(p.Glu541Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E541E) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.409
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 2 ACMG points.

PM1
In a domain Laminin EGF-like 1 (size 56) in uniprot entity USH2A_HUMAN there are 28 pathogenic changes around while only 2 benign (93%) in NM_206933.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15708226).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
USH2ANM_206933.4 linkuse as main transcriptc.1623G>C p.Glu541Asp missense_variant 9/72 ENST00000307340.8
USH2ANM_007123.6 linkuse as main transcriptc.1623G>C p.Glu541Asp missense_variant 9/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.1623G>C p.Glu541Asp missense_variant 9/721 NM_206933.4 P1O75445-1
USH2AENST00000366942.3 linkuse as main transcriptc.1623G>C p.Glu541Asp missense_variant 9/211 O75445-2
USH2AENST00000674083.1 linkuse as main transcriptc.1623G>C p.Glu541Asp missense_variant 9/73 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152024
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461636
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727124
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152024
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74228
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
0.27
DANN
Benign
0.95
DEOGEN2
Benign
0.085
T;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.26
N
LIST_S2
Benign
0.58
T;T
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.7
L;L
MutationTaster
Benign
0.84
D;D;D
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.91
N;N
REVEL
Benign
0.090
Sift
Benign
0.47
T;T
Sift4G
Benign
0.10
T;T
Polyphen
0.023
B;B
Vest4
0.22
MutPred
0.43
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP
0.76
MPC
0.030
ClinPred
0.054
T
GERP RS
-2.5
Varity_R
0.093
gMVP
0.43

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: rs146805130; hg19: chr1-216495246; API