4-75873263-G-C

Position:

• chr4-75873263-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006239.3(PPEF2):​c.1370C>G​(p.Ala457Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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: 2.74

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28239042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPEF2	NM_006239.3	c.1370C>G	p.Ala457Gly	missense_variant	12/17	ENST00000286719.12	NP_006230.2
PPEF2	XM_011532039.3	c.1370C>G	p.Ala457Gly	missense_variant	11/16		XP_011530341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPEF2	ENST00000286719.12	c.1370C>G	p.Ala457Gly	missense_variant	12/17	1	NM_006239.3	ENSP00000286719	P1
PPEF2	ENST00000511880.7	c.*1608C>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

Feb 16, 2023

The c.1370C>G (p.A457G) 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 1370, causing the alanine (A) at amino acid position 457 to be replaced by a glycine (G). 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	Benign	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T;.
Eigen	Benign	0.012
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.12
Sift	Benign	0.032	D;.
Sift4G	Uncertain	0.020	D;D
Polyphen		0.96	D;B
Vest4		0.29
MutPred		0.45		Gain of disorder (P = 0.0834);Gain of disorder (P = 0.0834);
MVP		0.50
MPC		0.58
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.21
gMVP		0.39

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: chr4-76794416;