6-42704529-A-T

Position:

• chr6-42704529-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Moderate

The NM_000322.5(PRPH2):​c.664T>A​(p.Cys222Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C222Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRPH2 NM_000322.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.26

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_000322.5 (PRPH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 866971
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr6-42704528-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 865759.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPH2	NM_000322.5	c.664T>A	p.Cys222Ser	missense_variant	2/3	ENST00000230381.7
PRPH2	XR_007059288.1	n.1109T>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPH2	ENST00000230381.7	c.664T>A	p.Cys222Ser	missense_variant	2/3	1	NM_000322.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

curation

Leiden Open Variation Database

Apr 06, 2021

Curator: Global Variome, with Curator vacancy. Submitter to LOVD: Manon Peeters. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.66	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-9.3	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.015	D
Vest4		0.98
MutPred		0.74		Gain of disorder (P = 5e-04);
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		5.1
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-42672267;