1-216097195-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_ModerateBP6BS2_Supporting

The NM_206933.4(USH2A):c.4646G>A(p.Arg1549Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,614,120 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1549P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.59

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a domain Laminin G-like 1 (size 192) in uniprot entity USH2A_HUMAN there are 48 pathogenic changes around while only 15 benign (76%) in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.21464711).

BP6

Variant 1-216097195-C-T is Benign according to our data. Variant chr1-216097195-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 73561.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.4646G>A	p.Arg1549Gln	missense_variant	Exon 22 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.4646G>A	p.Arg1549Gln	missense_variant	Exon 22 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.4646G>A	p.Arg1549Gln	missense_variant	Exon 22 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000458

AC:

115

AN:

251346

Hom.:

AF XY:

0.000398

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.000792

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000205

AC:

300

AN:

1461824

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

121

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00125

Gnomad4 NFE exome

AF:

0.000169

Gnomad4 OTH exome

AF:

0.000695

GnomAD4 genome

AF:

0.000112

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000241

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000717

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 31, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1549Gln variant in USH2A has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 0.12% (83/6669 6) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs190170807). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogen ic role. Conservation and computational prediction tools suggest that the p.Arg 1549Gln variant may not impact the protein, though this information is not predi ctive enough to rule out pathogenicity. In summary, the clinical significance o f the p.Arg1549Gln variant is uncertain. -

not provided

Benign:1

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.65

MetaRNN

Benign

0.21

MetaSVM

Uncertain

-0.13

MutationAssessor

Pathogenic

2.9

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.52

Sift

Benign

0.047

Sift4G

Uncertain

0.0090

Polyphen

0.73

Vest4

0.48

MVP

0.94

MPC

0.097

ClinPred

0.18

GERP RS

5.0

Varity_R

0.22

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over