chr6-42698407-C-T

Variant names:

• chr6-42698407-C-T
• rs425876
• NM_000322.5:c.929G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

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. 14/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 2.85
• Publications: 46 publications found

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

ACMG classification

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 2 benign, 14 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=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 VariationId is 138905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.929G>A	p.Arg310Lys	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.929G>A	p.Arg310Lys	missense	Exon 3 of 3	ENSP00000230381.5	P23942

Frequencies

GnomAD3 genomes AF: 0.927 AC: 140999 AN: 152128 Hom.: 65489 Cov.: 32

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

GnomAD2 exomes AF: 0.912 AC: 229405 AN: 251446 AF XY: 0.907

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 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.: 77 AF XY: 0.901 AC XY: 655597 AN XY: 727238

African (AFR) AF: 0.985 AC: 32970 AN: 33480

American (AMR) AF: 0.934 AC: 41755 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 22380 AN: 26134

East Asian (EAS) AF: 0.999 AC: 39655 AN: 39700

South Asian (SAS) AF: 0.874 AC: 75425 AN: 86258

European-Finnish (FIN) AF: 0.907 AC: 48437 AN: 53416

Middle Eastern (MID) AF: 0.857 AC: 4943 AN: 5768

European-Non Finnish (NFE) AF: 0.899 AC: 999636 AN: 1111996

Other (OTH) AF: 0.905 AC: 54684 AN: 60396

GnomAD4 genome AF: 0.927 AC: 141117 AN: 152246 Hom.: 65550 Cov.: 32 AF XY: 0.925 AC XY: 68832 AN XY: 74438

African (AFR) AF: 0.981 AC: 40766 AN: 41562

American (AMR) AF: 0.916 AC: 14011 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.862 AC: 2992 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5141 AN: 5148

South Asian (SAS) AF: 0.878 AC: 4242 AN: 4830

European-Finnish (FIN) AF: 0.904 AC: 9594 AN: 10614

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.901 AC: 61274 AN: 68006

Other (OTH) AF: 0.915 AC: 1936 AN: 2116

Alfa AF: 0.906 Hom.: 132111

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Patterned macular dystrophy 1 (3)
-	-	2	Choroidal dystrophy, central areolar 2 (2)
-	-	2	Pigmentary retinal dystrophy (2)
-	-	1	Adult-onset foveomacular vitelliform dystrophy (1)
-	-	1	Cone-rod dystrophy (1)
-	-	1	not provided (1)
-	-	1	PRPH2-related disorder (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 7 (1)
-	-	1	Vitelliform macular dystrophy 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.84
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.21	N
MetaRNN	Benign	6.3e-7	T
MetaSVM	Benign	-0.96	T
PhyloP100		2.8
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.010
MPC		0.31
ClinPred		0.072	T
GERP RS		5.4
gMVP		0.35
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs425876; hg19: chr6-42666145; COSMIC: COSV107216765; COSMIC: COSV107216765;