chr2-218634129-C-T

Variant names:

• chr2-218634129-C-T
• rs769313876
• NM_032726.4:c.1631C>T

Variant summary

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

The NM_032726.4(PLCD4):​c.1631C>T​(p.Thr544Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLCD4 NM_032726.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09

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]

ZNF142 (HGNC:12927): (zinc finger protein 142) The protein encoded by this gene belongs to the Kruppel family of C2H2-type zinc finger proteins. It contains 31 C2H2-type zinc fingers and may be involved in transcriptional regulation. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

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=0.27276343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCD4	NM_032726.4	c.1631C>T	p.Thr544Ile	missense_variant	Exon 12 of 16	ENST00000450993.7	NP_116115.1
ZNF142	NM_001379659.1	c.*4210G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000411696.7	NP_001366588.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCD4	ENST00000450993.7	c.1631C>T	p.Thr544Ile	missense_variant	Exon 12 of 16	1	NM_032726.4	ENSP00000388631.2
PLCD4	ENST00000432688.5	c.1727C>T	p.Thr576Ile	missense_variant	Exon 13 of 17	5		ENSP00000396185.1
PLCD4	ENST00000417849.5	c.1631C>T	p.Thr544Ile	missense_variant	Exon 12 of 17	5		ENSP00000396942.1
ZNF142	ENST00000411696	c.*4210G>A		3_prime_UTR_variant	Exon 11 of 11	5	NM_001379659.1	ENSP00000398798.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245494 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133080

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459704 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1631C>T (p.T544I) alteration is located in exon 12 (coding exon 11) of the PLCD4 gene. This alteration results from a C to T substitution at nucleotide position 1631, causing the threonine (T) at amino acid position 544 to be replaced by an isoleucine (I). 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	-0.23	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.31	T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.69	T;.;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.84	L;L;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.72	P;P;.
Vest4		0.23
MutPred		0.47		Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;
MVP		0.72
MPC		0.44
ClinPred		0.36	T
GERP RS		4.5
Varity_R		0.14
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs769313876; hg19: chr2-219498852;