rs200863393

Variant names:

• chr2-218618803-G-C
• rs200863393
• NM_032726.4:c.406G>C

Variant summary

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

The NM_032726.4(PLCD4):​c.406G>C​(p.Asp136His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,582,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: PLCD4 NM_032726.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.59
• Publications: 2 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCD4	NM_032726.4	c.406G>C	p.Asp136His	missense_variant	Exon 4 of 16	ENST00000450993.7	NP_116115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCD4	ENST00000450993.7	c.406G>C	p.Asp136His	missense_variant	Exon 4 of 16	1	NM_032726.4	ENSP00000388631.2
PLCD4	ENST00000432688.5	c.406G>C	p.Asp136His	missense_variant	Exon 4 of 17	5		ENSP00000396185.1
PLCD4	ENST00000417849.5	c.406G>C	p.Asp136His	missense_variant	Exon 4 of 17	5		ENSP00000396942.1
PLCD4	ENST00000444453.5	n.*93G>C		non_coding_transcript_exon_variant	Exon 4 of 5	4		ENSP00000415725.1
PLCD4	ENST00000446503.5	n.*93G>C		non_coding_transcript_exon_variant	Exon 4 of 6	4		ENSP00000406040.1
PLCD4	ENST00000444453.5	n.*93G>C		3_prime_UTR_variant	Exon 4 of 5	4		ENSP00000415725.1
PLCD4	ENST00000446503.5	n.*93G>C		3_prime_UTR_variant	Exon 4 of 6	4		ENSP00000406040.1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000308 AC: 61 AN: 198118 AF XY: 0.000338

Gnomad AFR exome AF: 0.000173

Gnomad AMR exome AF: 0.000107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000587

Gnomad NFE exome AF: 0.000339

Gnomad OTH exome AF: 0.000577

GnomAD4 exome AF: 0.000305 AC: 436 AN: 1430662 Hom.: 0 Cov.: 31 AF XY: 0.000329 AC XY: 233 AN XY: 708748

African (AFR) AF: 0.0000608 AC: 2 AN: 32900

American (AMR) AF: 0.0000763 AC: 3 AN: 39340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25550

East Asian (EAS) AF: 0.00 AC: 0 AN: 38198

South Asian (SAS) AF: 0.000548 AC: 45 AN: 82166

European-Finnish (FIN) AF: 0.000506 AC: 26 AN: 51434

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5724

European-Non Finnish (NFE) AF: 0.000306 AC: 335 AN: 1096044

Other (OTH) AF: 0.000405 AC: 24 AN: 59306

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74500

African (AFR) AF: 0.000216 AC: 9 AN: 41580

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000314 Hom.: 0

Bravo AF: 0.000212

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.000258 AC: 31

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.406G>C (p.D136H) alteration is located in exon 4 (coding exon 3) of the PLCD4 gene. This alteration results from a G to C substitution at nucleotide position 406, causing the aspartic acid (D) at amino acid position 136 to be replaced by a histidine (H). 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	0.23
BayesDel_addAF	Benign	-0.0024	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;D;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.1	M;M;.
PhyloP100		9.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.023	D;D;D
Sift4G	Benign	0.087	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.89
MVP		0.78
MPC		0.90
ClinPred		0.29	T
GERP RS		4.9
Varity_R		0.32
gMVP		0.37
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs200863393; hg19: chr2-219483526;