chr2-218621576-G-A

Variant names:

• chr2-218621576-G-A
• NM_032726.4:c.517G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032726.4(PLCD4):​c.517G>A​(p.Glu173Lys) 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. 14/24 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: PLCD4 NM_032726.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21
• Publications: 0 publications found

Genes affected

PLCD4 (HGNC:9062): (phospholipase C delta 4) This gene encodes a member of the delta class of phospholipase C enzymes. Phospholipase C enzymes play a critical role in many cellular processes by hydrolyzing phosphatidylinositol 4,5-bisphosphate into two intracellular second messengers, inositol 1,4,5-trisphosphate and diacylglycerol. Expression of this gene may be a marker for cancer. [provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCD4	NM_032726.4	c.517G>A	p.Glu173Lys	missense_variant	Exon 5 of 16	ENST00000450993.7	NP_116115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCD4	ENST00000450993.7	c.517G>A	p.Glu173Lys	missense_variant	Exon 5 of 16	1	NM_032726.4	ENSP00000388631.2
PLCD4	ENST00000432688.5	c.517G>A	p.Glu173Lys	missense_variant	Exon 5 of 17	5		ENSP00000396185.1
PLCD4	ENST00000417849.5	c.517G>A	p.Glu173Lys	missense_variant	Exon 5 of 17	5		ENSP00000396942.1
PLCD4	ENST00000446503.5	n.*141+63G>A		intron_variant	Intron 5 of 5	4		ENSP00000406040.1
PLCD4	ENST00000444453.5	n.*204G>A		downstream_gene_variant		4		ENSP00000415725.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.517G>A (p.E173K) alteration is located in exon 5 (coding exon 4) of the PLCD4 gene. This alteration results from a G to A substitution at nucleotide position 517, causing the glutamic acid (E) at amino acid position 173 to be replaced by a lysine (K). 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	0.083
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.49	T;.;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.0	M;M;.
PhyloP100		2.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.72	T;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.15	B;B;.
Vest4		0.22
MutPred		0.38		Gain of ubiquitination at E173 (P = 0.0185);Gain of ubiquitination at E173 (P = 0.0185);Gain of ubiquitination at E173 (P = 0.0185);
MVP		0.64
MPC		0.33
ClinPred		0.59	D
GERP RS		4.5
Varity_R		0.24
gMVP		0.20
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: 23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr2-219486299;