Genetic Variant USH2A:p.Val230Met (chr1-216365049-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_206933.4(USH2A):c.688G>A(p.Val230Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,613,260 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. V230L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 15 hom., cov: 32)

Exomes 𝑓: 0.021 ( 346 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: -0.0390

Publications

21 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 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Usher syndrome type 2
Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
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 -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.004126817).

BP6

Variant 1-216365049-C-T is Benign according to our data. Variant chr1-216365049-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48572.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.014 (2131/152212) while in subpopulation SAS AF = 0.0274 (132/4824). AF 95% confidence interval is 0.0236. There are 15 homozygotes in GnomAd4. There are 1070 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 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.688G>A	p.Val230Met	missense	Exon 4 of 72	NP_996816.3	O75445-1
	USH2A	NM_007123.6		c.688G>A	p.Val230Met	missense	Exon 4 of 21	NP_009054.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USH2A	ENST00000307340.8	TSL:1 MANE Select	c.688G>A	p.Val230Met	missense	Exon 4 of 72	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3	TSL:1	c.688G>A	p.Val230Met	missense	Exon 4 of 21	ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1		c.688G>A	p.Val230Met	missense	Exon 4 of 73	ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2131

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00439

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0273

Gnomad FIN

AF:

0.0218

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0193

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0152

AC:

3816

AN:

250800

AF XY:

0.0165

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00675

Gnomad ASJ exome

AF:

0.0154

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.0220

Gnomad NFE exome

AF:

0.0186

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.0206

AC:

30026

AN:

1461048

Hom.:

346

Cov.:

AF XY:

0.0206

AC XY:

14955

AN XY:

726812

show subpopulations

African (AFR)

AF:

0.00347

AC:

116

AN:

33454

American (AMR)

AF:

0.00707

AC:

316

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0151

AC:

393

AN:

26108

East Asian (EAS)

AF:

0.00406

AC:

161

AN:

39614

South Asian (SAS)

AF:

0.0221

AC:

1904

AN:

86146

European-Finnish (FIN)

AF:

0.0206

AC:

1100

AN:

53380

Middle Eastern (MID)

AF:

0.00538

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0223

AC:

24800

AN:

1111514

Other (OTH)

AF:

0.0200

AC:

1205

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

1547

3094

4642

6189

7736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

998

1996

2994

3992

4990

<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:

0.0140

AC:

2131

AN:

152212

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1070

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00438

AC:

182

AN:

41544

American (AMR)

AF:

0.0109

AC:

166

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3470

East Asian (EAS)

AF:

0.00231

AC:

AN:

5184

South Asian (SAS)

AF:

0.0274

AC:

132

AN:

4824

European-Finnish (FIN)

AF:

0.0218

AC:

231

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0193

AC:

1311

AN:

67988

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

105

210

316

421

526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0171

Hom.:

Bravo

AF:

0.0124

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0231

AC:

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0213

AC:

183

ExAC

AF:

0.0155

AC:

1878

Asia WGS

AF:

0.0270

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (4)

Retinal dystrophy (1)

Retinitis pigmentosa (1)

Usher syndrome type 2A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.1

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.14

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.4

PhyloP100

-0.039

PrimateAI

Benign

0.28

PROVEAN

Benign

0.0

REVEL

Benign

0.18

Sift

Benign

0.11

Sift4G

Benign

0.17

Polyphen

0.96

Vest4

0.054

MPC

0.072

ClinPred

0.0070

GERP RS

-1.4

Varity_R

0.029

gMVP

0.32

Mutation Taster

=98/2

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

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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