4-75873288-G-C

Position:

• chr4-75873288-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006239.3(PPEF2):​c.1345C>G​(p.Pro449Ala) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPEF2 NM_006239.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

Genes affected

PPEF2 (HGNC:9244): (protein phosphatase with EF-hand domain 2) This gene encodes a member of the serine/threonine protein phosphatase with EF-hand motif family. The protein contains a protein phosphatase catalytic domain, and at least two EF-hand calcium-binding motifs in its C terminus. Although its substrate(s) is unknown, the encoded protein, which is expressed specifically in photoreceptors and the pineal, has been suggested to play a role in the visual system. This gene shares high sequence similarity with the Drosophila retinal degeneration C (rdgC) gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPEF2	NM_006239.3	c.1345C>G	p.Pro449Ala	missense_variant	12/17	ENST00000286719.12	NP_006230.2
PPEF2	XM_011532039.3	c.1345C>G	p.Pro449Ala	missense_variant	11/16		XP_011530341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPEF2	ENST00000286719.12	c.1345C>G	p.Pro449Ala	missense_variant	12/17	1	NM_006239.3	ENSP00000286719	P1
PPEF2	ENST00000511880.7	c.*1583C>G		3_prime_UTR_variant, NMD_transcript_variant	13/18	1		ENSP00000426186

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2024

The c.1345C>G (p.P449A) alteration is located in exon 12 (coding exon 11) of the PPEF2 gene. This alteration results from a C to G substitution at nucleotide position 1345, causing the proline (P) at amino acid position 449 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	4.2	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-7.7	D;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.026	D;.
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.68
MutPred		0.76		Gain of MoRF binding (P = 0.1731);Gain of MoRF binding (P = 0.1731);
MVP		0.82
MPC		0.64
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.44
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr4-76794441;