rs61755800

Variant names:

• chr6-42704559-T-C
• rs61755800
• NM_000322.5:c.634A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-42704559-T-C
• chr6-42704559-T-G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000322.5(PRPH2):​c.634A>G​(p.Ser212Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S212T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRPH2 NM_000322.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.96
• Publications: 13 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
• Leber congenital amaurosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• retinitis pigmentosa 7

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• PRPH2-related retinopathy

  Inheritance: SD, AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• choroidal dystrophy, central areolar 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 41 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000322.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-42704558-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 98690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 6-42704559-T-C is Pathogenic according to our data. Variant chr6-42704559-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 98689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.634A>G	p.Ser212Gly	missense	Exon 2 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.634A>G	p.Ser212Gly	missense	Exon 2 of 3	ENSP00000230381.5	P23942

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (3)
2	-	-	Retinal dystrophy (2)
2	-	-	Retinitis pigmentosa (2)
1	-	-	PRPH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.86	D
PhyloP100		8.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Vest4		0.98
MutPred		0.73		Loss of glycosylation at S212 (P = 0.0485)
MVP		0.99
MPC		0.98
ClinPred		1.0	D
GERP RS		5.1
gMVP		0.95
Mutation Taster		=16/84	disease causing (ClinVar)

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: rs61755800; hg19: chr6-42672297;