6-42698426-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000322.5(PRPH2):c.910C>G(p.Gln304Glu) variant causes a missense change. The variant allele was found at a frequency of 0.787 in 1,613,930 control chromosomes in the GnomAD database, including 501,175 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q304P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.77 ( 45505 hom., cov: 32)

Exomes 𝑓: 0.79 ( 455670 hom. )

Consequence

PRPH2
NM_000322.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: 6.12

Publications

50 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, SD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
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
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)
inherited retinal dystrophy
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
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 -17 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, 10 uncertain in NM_000322.5

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 126 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 0.10182 (below the threshold of 3.09). Trascript score misZ: 0.57529 (below the threshold of 3.09). GenCC associations: The gene is linked to inherited retinal dystrophy, fundus albipunctatus, retinitis pigmentosa 7, choroidal dystrophy, central areolar 2, adult-onset foveomacular vitelliform dystrophy, retinitis punctata albescens, hereditary macular dystrophy, central areolar choroidal dystrophy, Leber congenital amaurosis, vitelliform macular dystrophy 3, multifocal pattern dystrophy simulating fundus flavimaculatus, PRPH2-related retinopathy, cone-rod dystrophy, retinitis pigmentosa, patterned macular dystrophy.

BP4

Computational evidence support a benign effect (MetaRNN=1.8733482E-6).

BP6

Variant 6-42698426-G-C is Benign according to our data. Variant chr6-42698426-G-C is described in ClinVar as Benign. ClinVar VariationId is 138904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000322.5. 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
	PRPH2	NM_000322.5	MANE Select	c.910C>G	p.Gln304Glu	missense	Exon 3 of 3	NP_000313.2	P23942

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPH2	ENST00000230381.7	TSL:1 MANE Select	c.910C>G	p.Gln304Glu	missense	Exon 3 of 3	ENSP00000230381.5	P23942

Frequencies

GnomAD3 genomes

AF:

0.773

AC:

117437

AN:

151970

Hom.:

45469

Cov.:

show subpopulations

Gnomad AFR

AF:

0.732

Gnomad AMI

AF:

0.932

Gnomad AMR

AF:

0.741

Gnomad ASJ

AF:

0.715

Gnomad EAS

AF:

0.856

Gnomad SAS

AF:

0.736

Gnomad FIN

AF:

0.784

Gnomad MID

AF:

0.772

Gnomad NFE

AF:

0.801

Gnomad OTH

AF:

0.756

GnomAD2 exomes

AF:

0.775

AC:

194836

AN:

251440

AF XY:

0.775

show subpopulations

Gnomad AFR exome

AF:

0.730

Gnomad AMR exome

AF:

0.714

Gnomad ASJ exome

AF:

0.698

Gnomad EAS exome

AF:

0.861

Gnomad FIN exome

AF:

0.791

Gnomad NFE exome

AF:

0.799

Gnomad OTH exome

AF:

0.775

GnomAD4 exome

AF:

0.789

AC:

1152883

AN:

1461842

Hom.:

455670

Cov.:

AF XY:

0.787

AC XY:

572507

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.731

AC:

24460

AN:

33478

American (AMR)

AF:

0.715

AC:

31989

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.700

AC:

18305

AN:

26134

East Asian (EAS)

AF:

0.847

AC:

33637

AN:

39700

South Asian (SAS)

AF:

0.739

AC:

63727

AN:

86256

European-Finnish (FIN)

AF:

0.800

AC:

42740

AN:

53416

Middle Eastern (MID)

AF:

0.769

AC:

4433

AN:

5768

European-Non Finnish (NFE)

AF:

0.797

AC:

886208

AN:

1111974

Other (OTH)

AF:

0.785

AC:

47384

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

15687

31374

47062

62749

78436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20720

41440

62160

82880

103600

<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:

0.773

AC:

117524

AN:

152088

Hom.:

45505

Cov.:

AF XY:

0.769

AC XY:

57175

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.732

AC:

30372

AN:

41492

American (AMR)

AF:

0.740

AC:

11315

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.715

AC:

2480

AN:

3470

East Asian (EAS)

AF:

0.856

AC:

4394

AN:

5134

South Asian (SAS)

AF:

0.736

AC:

3547

AN:

4818

European-Finnish (FIN)

AF:

0.784

AC:

8296

AN:

10582

Middle Eastern (MID)

AF:

0.776

AC:

228

AN:

294

European-Non Finnish (NFE)

AF:

0.801

AC:

54437

AN:

67984

Other (OTH)

AF:

0.760

AC:

1605

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1388

2777

4165

5554

6942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

860

1720

2580

3440

4300

<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:

0.785

Hom.:

32196

Bravo

AF:

0.768

TwinsUK

AF:

0.777

AC:

2880

ALSPAC

AF:

0.781

AC:

3010

ESP6500AA

AF:

0.729

AC:

3214

ESP6500EA

AF:

0.801

AC:

6889

ExAC

AF:

0.777

AC:

94374

Asia WGS

AF:

0.804

AC:

2799

AN:

3478

EpiCase

AF:

0.792

EpiControl

AF:

0.793

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Patterned macular dystrophy 1 (3)

Choroidal dystrophy, central areolar 2 (2)

Pigmentary retinal dystrophy (2)

Adult-onset foveomacular vitelliform dystrophy (1)

Cone-rod dystrophy (1)

PRPH2-related disorder (1)

Retinal dystrophy (1)

Retinitis pigmentosa (1)

Retinitis pigmentosa 7 (1)

Vitelliform macular dystrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.037

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.76

Eigen

Benign

-0.073

Eigen_PC

Benign

0.0096

FATHMM_MKL

Benign

0.15

MetaRNN

Benign

0.0000019

MetaSVM

Benign

-1.0

PhyloP100

6.1

PrimateAI

Benign

0.45

PROVEAN

Benign

0.99

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.017

MPC

0.33

ClinPred

0.042

GERP RS

5.4

gMVP

0.36

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over