1-216072904-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_206933.4(USH2A):​c.5842C>A​(p.Arg1948Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,588 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1948C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

4
10
5

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 7.36
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_pathogenic. Variant got 6 ACMG points.

PM1
In a domain Fibronectin type-III 5 (size 86) in uniprot entity USH2A_HUMAN there are 20 pathogenic changes around while only 4 benign (83%) in NM_206933.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USH2ANM_206933.4 linkuse as main transcriptc.5842C>A p.Arg1948Ser missense_variant 29/72 ENST00000307340.8 NP_996816.3 O75445-1
USH2A-AS2NR_125992.1 linkuse as main transcriptn.136+304G>T intron_variant
USH2A-AS2NR_125993.1 linkuse as main transcriptn.136+304G>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.5842C>A p.Arg1948Ser missense_variant 29/721 NM_206933.4 ENSP00000305941.3 O75445-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461588
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727108
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Retinal dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2016- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 09, 2022In 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. 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. This variant has not been reported in the literature in individuals affected with USH2A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 1948 of the USH2A protein (p.Arg1948Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.070
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.77
T
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.85
D
MetaSVM
Benign
-0.72
T
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Benign
0.36
T
PROVEAN
Uncertain
-3.4
D
REVEL
Uncertain
0.33
Sift
Uncertain
0.0060
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.79
MutPred
0.39
Gain of glycosylation at R1948 (P = 0.0062);
MVP
0.95
MPC
0.24
ClinPred
1.0
D
GERP RS
6.0
Varity_R
0.38
gMVP
0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-216246246; API