6-42698323-T-C

Position:

chr6-42698323-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000322.5(PRPH2):c.1013A>G(p.Asp338Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 1,613,846 control chromosomes in the GnomAD database, including 502,174 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D338E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.77 ( 45659 hom., cov: 31)

Exomes 𝑓: 0.79 ( 456515 hom. )

Consequence

PRPH2
NM_000322.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 1.27

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.6911155E-7).

BP6

Variant 6-42698323-T-C is Benign according to our data. Variant chr6-42698323-T-C is described in ClinVar as [Benign]. Clinvar id is 138906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42698323-T-C is described in Lovd as [Benign]. Variant chr6-42698323-T-C is described in Lovd as [Pathogenic]. Variant chr6-42698323-T-C is described in Lovd as [Likely_benign]. Variant chr6-42698323-T-C is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPH2	NM_000322.5 linkuse as main transcript	c.1013A>G	p.Asp338Gly	missense_variant	3/3	ENST00000230381.7	NP_000313.2	P23942

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPH2	ENST00000230381.7 linkuse as main transcript	c.1013A>G	p.Asp338Gly	missense_variant	3/3	1	NM_000322.5	ENSP00000230381.5		P23942

Frequencies

GnomAD3 genomes

AF:

0.774

AC:

117622

AN:

151942

Hom.:

45623

Cov.:

show subpopulations

Gnomad AFR

AF:

0.732

Gnomad AMI

AF:

0.932

Gnomad AMR

AF:

0.740

Gnomad ASJ

AF:

0.715

Gnomad EAS

AF:

0.858

Gnomad SAS

AF:

0.737

Gnomad FIN

AF:

0.800

Gnomad MID

AF:

0.772

Gnomad NFE

AF:

0.801

Gnomad OTH

AF:

0.757

GnomAD3 exomes

AF:

0.776

AC:

194604

AN:

250756

Hom.:

75811

AF XY:

0.776

AC XY:

105291

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.731

Gnomad AMR exome

AF:

0.713

Gnomad ASJ exome

AF:

0.698

Gnomad EAS exome

AF:

0.862

Gnomad SAS exome

AF:

0.743

Gnomad FIN exome

AF:

0.802

Gnomad NFE exome

AF:

0.799

Gnomad OTH exome

AF:

0.776

GnomAD4 exome

AF:

0.789

AC:

1153927

AN:

1461786

Hom.:

456515

Cov.:

AF XY:

0.788

AC XY:

573068

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.731

Gnomad4 AMR exome

AF:

0.714

Gnomad4 ASJ exome

AF:

0.700

Gnomad4 EAS exome

AF:

0.849

Gnomad4 SAS exome

AF:

0.740

Gnomad4 FIN exome

AF:

0.810

Gnomad4 NFE exome

AF:

0.797

Gnomad4 OTH exome

AF:

0.785

GnomAD4 genome

AF:

0.774

AC:

117709

AN:

152060

Hom.:

45659

Cov.:

AF XY:

0.771

AC XY:

57335

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.732

Gnomad4 AMR

AF:

0.740

Gnomad4 ASJ

AF:

0.715

Gnomad4 EAS

AF:

0.858

Gnomad4 SAS

AF:

0.737

Gnomad4 FIN

AF:

0.800

Gnomad4 NFE

AF:

0.801

Gnomad4 OTH

AF:

0.760

Alfa

AF:

0.789

Hom.:

93999

Bravo

AF:

0.768

TwinsUK

AF:

0.777

AC:

2881

ALSPAC

AF:

0.781

AC:

3009

ESP6500AA

AF:

0.729

AC:

3213

ESP6500EA

AF:

0.801

AC:

6890

ExAC

AF:

0.778

AC:

94455

Asia WGS

AF:

0.805

AC:

2801

AN:

3478

EpiCase

AF:

0.792

EpiControl

AF:

0.793

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2011	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Pigmentary retinal dystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Choroidal dystrophy, central areolar 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Vitelliform macular dystrophy 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Retinitis pigmentosa 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Cone-rod dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided

Benign:1

Likely benign, no assertion criteria provided

literature only

Department of Ophthalmology and Visual Sciences Kyoto University

- -

PRPH2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Adult-onset foveomacular vitelliform dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.92

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.53

MetaRNN

Benign

8.7e-7

MetaSVM

Benign

-0.88

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.17

REVEL

Benign

0.028

Sift

Benign

0.25

Sift4G

Benign

0.41

Vest4

0.034

MPC

0.40

ClinPred

0.036

GERP RS

4.3

gMVP

0.42

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over