1-215934756-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_206933.4(USH2A):c.7160T>C(p.Met2387Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000731 in 1,612,662 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.14

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023505151).

BP6

Variant 1-215934756-A-G is Benign according to our data. Variant chr1-215934756-A-G is described in ClinVar as Benign. ClinVar VariationId is 48578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00403 (613/152118) while in subpopulation AFR AF = 0.0142 (589/41546). AF 95% confidence interval is 0.0132. There are 6 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206933.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.7160T>C	p.Met2387Thr	missense	Exon 38 of 72	NP_996816.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.7160T>C	p.Met2387Thr	missense	Exon 38 of 72	ENSP00000305941.3
	USH2A	ENST00000674083.1		c.7160T>C	p.Met2387Thr	missense	Exon 38 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes

AF:

0.00402

AC:

611

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000921

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.000973

AC:

244

AN:

250850

AF XY:

0.000590

show subpopulations

Gnomad AFR exome

AF:

0.0137

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000388

AC:

566

AN:

1460544

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

236

AN XY:

726562

show subpopulations

African (AFR)

AF:

0.0144

AC:

482

AN:

33414

American (AMR)

AF:

0.000470

AC:

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111056

Other (OTH)

AF:

0.000531

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

AF:

0.00403

AC:

613

AN:

152118

Hom.:

Cov.:

AF XY:

0.00370

AC XY:

275

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0142

AC:

589

AN:

41546

American (AMR)

AF:

0.000920

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67966

Other (OTH)

AF:

0.00285

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00152

Hom.:

Bravo

AF:

0.00450

ESP6500AA

AF:

0.0132

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00127

AC:

154

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Usher syndrome type 2A (2)

Retinitis pigmentosa 39 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.11

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.44

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

5.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.8

REVEL

Benign

0.099

Sift

Uncertain

0.019

Sift4G

Uncertain

0.0050

Polyphen

0.45

Vest4

0.48

MVP

0.60

MPC

0.041

ClinPred

0.035

GERP RS

4.5

Varity_R

0.24

gMVP

0.40

Mutation Taster

=94/6

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over