chr6-42722017-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000322.5(PRPH2):c.318T>C(p.Val106Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 1,613,784 control chromosomes in the GnomAD database, including 269,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 27013 hom., cov: 31)

Exomes 𝑓: 0.57 ( 242124 hom. )

Consequence

PRPH2
NM_000322.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 1.04

Publications

29 publications found

Variant links:

Genes affected

PRPH2 (HGNC:9942): (peripherin 2) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein found in the outer segment of both rod and cone photoreceptor cells. It may function as an adhesion molecule involved in stabilization and compaction of outer segment disks or in the maintenance of the curvature of the rim. This protein is essential for disk morphogenesis. Defects in this gene are associated with both central and peripheral retinal degenerations. Some of the various phenotypically different disorders are autosomal dominant retinitis pigmentosa, progressive macular degeneration, macular dystrophy and retinitis pigmentosa digenic. [provided by RefSeq, Jul 2008]

PRPH2 Gene-Disease associations (from GenCC):

hereditary macular dystrophy
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
PRPH2-related retinopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
Leber congenital amaurosis
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
retinitis pigmentosa 7
Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
inherited retinal dystrophy
Inheritance: SD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, Ambry Genetics
choroidal dystrophy, central areolar 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
fundus albipunctatus
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
vitelliform macular dystrophy 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
adult-onset foveomacular vitelliform dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
central areolar choroidal dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
multifocal pattern dystrophy simulating fundus flavimaculatus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
patterned macular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis punctata albescens
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PRPH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 6-42722017-A-G is Benign according to our data. Variant chr6-42722017-A-G is described in ClinVar as [Benign]. Clinvar id is 92846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPH2	NM_000322.5 link	c.318T>C	p.Val106Val	synonymous_variant	Exon 1 of 3	ENST00000230381.7	NP_000313.2	P23942
PRPH2	XR_007059288.1 link	n.581T>C		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPH2	ENST00000230381.7 link	c.318T>C	p.Val106Val	synonymous_variant	Exon 1 of 3	1	NM_000322.5	ENSP00000230381.5		P23942

Frequencies

GnomAD3 genomes

AF:

0.595

AC:

90337

AN:

151804

Hom.:

26977

Cov.:

show subpopulations

Gnomad AFR

AF:

0.656

Gnomad AMI

AF:

0.734

Gnomad AMR

AF:

0.594

Gnomad ASJ

AF:

0.531

Gnomad EAS

AF:

0.577

Gnomad SAS

AF:

0.518

Gnomad FIN

AF:

0.553

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.573

Gnomad OTH

AF:

0.595

GnomAD2 exomes

AF:

0.578

AC:

145040

AN:

251124

AF XY:

0.574

show subpopulations

Gnomad AFR exome

AF:

0.655

Gnomad AMR exome

AF:

0.603

Gnomad ASJ exome

AF:

0.521

Gnomad EAS exome

AF:

0.590

Gnomad FIN exome

AF:

0.560

Gnomad NFE exome

AF:

0.577

Gnomad OTH exome

AF:

0.579

GnomAD4 exome

AF:

0.574

AC:

839587

AN:

1461860

Hom.:

242124

Cov.:

AF XY:

0.573

AC XY:

416708

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.659

AC:

22064

AN:

33480

American (AMR)

AF:

0.602

AC:

26915

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.521

AC:

13629

AN:

26136

East Asian (EAS)

AF:

0.528

AC:

20969

AN:

39700

South Asian (SAS)

AF:

0.537

AC:

46319

AN:

86256

European-Finnish (FIN)

AF:

0.562

AC:

30044

AN:

53418

Middle Eastern (MID)

AF:

0.627

AC:

3619

AN:

5768

European-Non Finnish (NFE)

AF:

0.577

AC:

641160

AN:

1111990

Other (OTH)

AF:

0.577

AC:

34868

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

26751

53503

80254

107006

133757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17790

35580

53370

71160

88950

<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:

0.595

AC:

90426

AN:

151924

Hom.:

27013

Cov.:

AF XY:

0.592

AC XY:

43936

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.656

AC:

27170

AN:

41426

American (AMR)

AF:

0.593

AC:

9045

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.531

AC:

1843

AN:

3468

East Asian (EAS)

AF:

0.577

AC:

2972

AN:

5150

South Asian (SAS)

AF:

0.519

AC:

2500

AN:

4818

European-Finnish (FIN)

AF:

0.553

AC:

5828

AN:

10540

Middle Eastern (MID)

AF:

0.639

AC:

188

AN:

294

European-Non Finnish (NFE)

AF:

0.573

AC:

38954

AN:

67966

Other (OTH)

AF:

0.598

AC:

1261

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1869

3738

5608

7477

9346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

760

1520

2280

3040

3800

<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:

0.581

Hom.:

24920

Bravo

AF:

0.607

Asia WGS

AF:

0.557

AC:

1942

AN:

3478

EpiCase

AF:

0.579

EpiControl

AF:

0.580

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 28, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 21, 2021

Leiden Open Variation Database

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:curation

Curator: Global Variome, with Curator vacancy. Submitter to LOVD: Julia Lopez. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 20, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Pigmentary retinal dystrophy

Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Patterned macular dystrophy 1

Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Choroidal dystrophy, central areolar 2

Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Vitelliform macular dystrophy 3

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 7

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cone-rod dystrophy

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PRPH2-related disorder

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Adult-onset foveomacular vitelliform dystrophy

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Retinitis pigmentosa

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

2.5

(source)

DANN

Benign

0.44

PhyloP100

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over