Variant 1-216289317-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_206933.4(USH2A):c.1934C>G(p.Thr645Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,828 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T645I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.223

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]

USH2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a domain Laminin EGF-like 3 (size 52) in uniprot entity USH2A_HUMAN there are 18 pathogenic changes around while only 2 benign (90%) in NM_206933.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036214113).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.1934C>G	p.Thr645Arg	missense_variant	11/72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 linkuse as main transcript	c.1934C>G	p.Thr645Arg	missense_variant	11/21		NP_009054.6	O75445-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.1934C>G	p.Thr645Arg	missense_variant	11/72	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.1934C>G	p.Thr645Arg	missense_variant	11/21	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.1934C>G	p.Thr645Arg	missense_variant	11/73			ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251314

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000291

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000177

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.000246

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.0

DANN

Benign

0.55

DEOGEN2

Benign

0.020

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.036

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

0.090

N;N

REVEL

Benign

0.042

Sift

Benign

0.56

T;T

Sift4G

Benign

0.48

T;T

Polyphen

0.0

B;B

Vest4

0.19

MutPred

0.50

Gain of disorder (P = 0.0782);Gain of disorder (P = 0.0782);

MVP

0.79

MPC

0.032

ClinPred

0.0063

GERP RS

0.35

Varity_R

0.044

gMVP

0.47

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over