7-5199650-A-C

Position:

• chr7-5199650-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001278299.2(WIPI2):​c.-230A>C variant causes a 5 prime UTR premature start codon gain 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: WIPI2 NM_001278299.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.79

Genes affected

WIPI2 (HGNC:32225): (WD repeat domain, phosphoinositide interacting 2) WD40 repeat proteins are key components of many essential biologic functions. They regulate the assembly of multiprotein complexes by presenting a beta-propeller platform for simultaneous and reversible protein-protein interactions. Members of the WIPI subfamily of WD40 repeat proteins, such as WIPI2, have a 7-bladed propeller structure and contain a conserved motif for interaction with phospholipids (Proikas-Cezanne et al., 2004 [PubMed 15602573]).[supplied by OMIM, Mar 2008]

WIPI2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WIPI2	NM_015610.4	c.203A>C	p.Tyr68Ser	missense_variant	3/13	ENST00000288828.9	NP_056425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WIPI2	ENST00000288828.9	c.203A>C	p.Tyr68Ser	missense_variant	3/13	1	NM_015610.4	ENSP00000288828.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 19, 2024

The c.203A>C (p.Y68S) alteration is located in exon 3 (coding exon 3) of the WIPI2 gene. This alteration results from a A to C substitution at nucleotide position 203, causing the tyrosine (Y) at amino acid position 68 to be replaced by a serine (S). 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	0.89
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.6	M;.;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.0	D;D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		0.035	B;B;B;D
Vest4		0.84
MutPred		0.66		Gain of disorder (P = 0.0052);.;Gain of disorder (P = 0.0052);.;
MVP		0.75
MPC		1.3
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs1781928268; hg19: chr7-5239281;