6-42698407-C-T

Position:

chr6-42698407-C-T

Variant summary

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

The NM_000322.5(PRPH2):c.929G>A(p.Arg310Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.905 in 1,614,118 control chromosomes in the GnomAD database, including 662,152 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. R310E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.93 ( 65550 hom., cov: 32)

Exomes 𝑓: 0.90 ( 596602 hom. )

Consequence

PRPH2
NM_000322.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:22

Conservation

PhyloP100: 2.85

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=6.280708E-7).

BP6

Variant 6-42698407-C-T is Benign according to our data. Variant chr6-42698407-C-T is described in ClinVar as [Benign]. Clinvar id is 138905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42698407-C-T is described in Lovd as [Benign]. Variant chr6-42698407-C-T is described in Lovd as [Likely_benign]. Variant chr6-42698407-C-T is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPH2	NM_000322.5 linkuse as main transcript	c.929G>A	p.Arg310Lys	missense_variant	3/3	ENST00000230381.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPH2	ENST00000230381.7 linkuse as main transcript	c.929G>A	p.Arg310Lys	missense_variant	3/3	1	NM_000322.5	P1

Frequencies

GnomAD3 genomes

AF:

0.927

AC:

140999

AN:

152128

Hom.:

65489

Cov.:

show subpopulations

Gnomad AFR

AF:

0.981

Gnomad AMI

AF:

0.986

Gnomad AMR

AF:

0.916

Gnomad ASJ

AF:

0.862

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.879

Gnomad FIN

AF:

0.904

Gnomad MID

AF:

0.889

Gnomad NFE

AF:

0.901

Gnomad OTH

AF:

0.914

GnomAD3 exomes

AF:

0.912

AC:

229405

AN:

251446

Hom.:

104954

AF XY:

0.907

AC XY:

123237

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.983

Gnomad AMR exome

AF:

0.936

Gnomad ASJ exome

AF:

0.853

Gnomad EAS exome

AF:

0.998

Gnomad SAS exome

AF:

0.877

Gnomad FIN exome

AF:

0.902

Gnomad NFE exome

AF:

0.899

Gnomad OTH exome

AF:

0.894

GnomAD4 exome

AF:

0.903

AC:

1319885

AN:

1461872

Hom.:

596602

Cov.:

AF XY:

0.901

AC XY:

655597

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.985

Gnomad4 AMR exome

AF:

0.934

Gnomad4 ASJ exome

AF:

0.856

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.874

Gnomad4 FIN exome

AF:

0.907

Gnomad4 NFE exome

AF:

0.899

Gnomad4 OTH exome

AF:

0.905

GnomAD4 genome

AF:

0.927

AC:

141117

AN:

152246

Hom.:

65550

Cov.:

AF XY:

0.925

AC XY:

68832

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.981

Gnomad4 AMR

AF:

0.916

Gnomad4 ASJ

AF:

0.862

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.878

Gnomad4 FIN

AF:

0.904

Gnomad4 NFE

AF:

0.901

Gnomad4 OTH

AF:

0.915

Alfa

AF:

0.904

Hom.:

99968

Bravo

AF:

0.933

TwinsUK

AF:

0.896

AC:

3321

ALSPAC

AF:

0.892

AC:

3436

ESP6500AA

AF:

0.980

AC:

4319

ESP6500EA

AF:

0.905

AC:

7786

ExAC

AF:

0.912

AC:

110689

Asia WGS

AF:

0.955

AC:

3320

AN:

3478

EpiCase

AF:

0.895

EpiControl

AF:

0.894

ClinVar

Significance: Benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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	Eurofins Ntd Llc (ga)	Apr 28, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Mar 21, 2021	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Julia Lopez, Yoshito Koyanagi. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

Patterned macular dystrophy 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 12, 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. -

Pigmentary retinal dystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -

Choroidal dystrophy, central areolar 2

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 12, 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. -

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 12, 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

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

PRPH2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Adult-onset foveomacular vitelliform dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.84

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.070

FATHMM_MKL

Benign

0.21

MetaRNN

Benign

6.3e-7

MetaSVM

Benign

-0.96

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

1.1

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.010

MPC

0.31

ClinPred

0.072

GERP RS

5.4

gMVP

0.35

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