rs869312182

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM3PP4PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_206933.4:c.6446C>A variant in the USH2A gene is a missense variant predicted to cause the substitution of proline by glutamine at amino acid 2149 (p.Pro2149Gln). The minor allele frequency of this variant in gnomAD v.4.1.0 was 0.00059% (7/1179718 alleles) in the European (non-Finnish) population meeting PM2_Supporting. The REVEL computational prediction analysis tool produced a score of 0.355, which doesn’t meet either of the thresholds necessary to apply PP3/BP4. It has been detected with another suspected pathogenic variant in two patients with Usher syndrome type 2, of which one patient displayed hearing loss with an onset in the first decade and retinitis pigmentosa with an onset at 22y.o, which is specific for Usher syndrome (PM3, PP4; PMIDs: 26872967, 29074561, 32176120, 31836858). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: PM3, PM2_Supporting, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 4/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA354063/MONDO:0019501/005

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:2

Conservation

PhyloP100: 6.28

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 39
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

USH2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.6446C>A	p.Pro2149Gln	missense_variant	Exon 33 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.6446C>A	p.Pro2149Gln	missense_variant	Exon 33 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1 link	c.6446C>A	p.Pro2149Gln	missense_variant	Exon 33 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461376

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111696

Other (OTH)

AF:

0.00

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Usher syndrome type 2A

Pathogenic:1

Aug 28, 2015

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinitis pigmentosa

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Usher syndrome

Uncertain:1

Apr 16, 2025

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The NM_206933.4:c.6446C>A variant in the USH2A gene is a missense variant predicted to cause the substitution of proline by glutamine at amino acid 2149 (p.Pro2149Gln). The minor allele frequency of this variant in gnomAD v.4.1.0 was 0.00059% (7/1179718 alleles) in the European (non-Finnish) population meeting PM2_Supporting. The REVEL computational prediction analysis tool produced a score of 0.355, which doesn’t meet either of the thresholds necessary to apply PP3/BP4. It has been detected with another suspected pathogenic variant in two patients with Usher syndrome type 2, of which one patient displayed hearing loss with an onset in the first decade and retinitis pigmentosa with an onset at 22y.o, which is specific for Usher syndrome (PM3, PP4; PMIDs: 26872967, 29074561, 32176120, 31836858). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: PM3, PM2_Supporting, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 4/16/2025). -

Retinal dystrophy

Uncertain:1

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.34

MutationAssessor

Pathogenic

3.0

PhyloP100

6.3

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MutPred

0.34

Loss of glycosylation at S2148 (P = 0.08);

MVP

0.95

MPC

0.23

ClinPred

1.0

GERP RS

5.0

Varity_R

0.66

gMVP

0.76

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over