1-215674179-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_206933.4(USH2A):ā€‹c.13732A>Gā€‹(p.Lys4578Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K4578Q) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.000045 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 2.10
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08273384).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
USH2ANM_206933.4 linkuse as main transcriptc.13732A>G p.Lys4578Glu missense_variant 63/72 ENST00000307340.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.13732A>G p.Lys4578Glu missense_variant 63/721 NM_206933.4 P1O75445-1
USH2AENST00000674083.1 linkuse as main transcriptc.13732A>G p.Lys4578Glu missense_variant 63/73 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000517
AC:
13
AN:
251326
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135820
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000616
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000451
AC:
66
AN:
1461870
Hom.:
0
Cov.:
30
AF XY:
0.0000468
AC XY:
34
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000134
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:
0.0000522
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000847
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000576
AC:
7
EpiCase
AF:
0.000273
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Usher syndrome type 2A Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Nov 11, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabNov 04, 2023- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 08, 2016Variant classified as Uncertain Significance - Favor Benign. The p.Lys4578Glu va riant in USH2A has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 4/11568 of Latino chromosomes and 3/66732 of European chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs765354805). The lysine (Lys) at position 457 8 is not conserved in mammals or evolutionarily distant species and 2 mammals (c ape elephant shrew and opossum) carry a glutamic acid (Glu) at this position, ra ising the possibility that this change may be tolerated. Additional computationa l prediction tools do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Lys4578Glu varian t is uncertain, its presence in mammals suggests that it is more likely to be be nign. -
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 13, 2021- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 06, 2022This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 4578 of the USH2A protein (p.Lys4578Glu). This variant is present in population databases (rs765354805, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 229620). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 submitterclinical testingBlueprint GeneticsJun 09, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
15
DANN
Benign
0.56
DEOGEN2
Benign
0.049
T
Eigen
Benign
-0.82
Eigen_PC
Benign
-0.73
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.54
T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.083
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-1.0
N
REVEL
Benign
0.055
Sift
Benign
0.46
T
Sift4G
Benign
0.092
T
Polyphen
0.012
B
Vest4
0.11
MutPred
0.48
Loss of methylation at K4578 (P = 0.0104);
MVP
0.85
MPC
0.038
ClinPred
0.027
T
GERP RS
2.6
Varity_R
0.080
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs765354805; hg19: chr1-215847521; API