chr3-38008262-G-A

Variant names:

• chr3-38008262-G-A
• rs752980022
• NM_006225.4:c.2008C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006225.4(PLCD1):​c.2008C>T​(p.Arg670Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R670H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PLCD1 NM_006225.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23
• Publications: 1 publications found

Genes affected

PLCD1 (HGNC:9060): (phospholipase C delta 1) This gene encodes a member of the phospholipase C family. Phospholipase C isozymes play critical roles in intracellular signal transduction by catalyzing the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers diacylglycerol (DAG) and inositol triphosphate (IP3). The encoded protein functions as a tumor suppressor in several types of cancer, and mutations in this gene are a cause of hereditary leukonychia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

PLCD1 Gene-Disease associations (from GenCC):

• nonsyndromic congenital nail disorder 3

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2609258).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006225.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCD1	NM_006225.4	MANE Select	c.2008C>T	p.Arg670Cys	missense	Exon 13 of 15	NP_006216.2	A0A384MR47
	PLCD1	NM_001130964.2		c.2071C>T	p.Arg691Cys	missense	Exon 13 of 15	NP_001124436.1	P51178-2
	PLCD1	NR_024071.2		n.2235C>T		non_coding_transcript_exon	Exon 12 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCD1	ENST00000334661.5	TSL:1 MANE Select	c.2008C>T	p.Arg670Cys	missense	Exon 13 of 15	ENSP00000335600.4	P51178-1
	PLCD1	ENST00000463876.5	TSL:2	c.2071C>T	p.Arg691Cys	missense	Exon 13 of 15	ENSP00000430344.1	P51178-2
	PLCD1	ENST00000956065.1		c.2005C>T	p.Arg669Cys	missense	Exon 13 of 15	ENSP00000626124.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251366 AF XY: 0.0000589

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461788 Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19 AN XY: 727208

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1112002

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

African (AFR) AF: 0.0000241 AC: 1 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.2
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.26
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.96	D
Vest4		0.14
MutPred		0.58		Loss of disorder (P = 0.0317)
MVP		0.75
MPC		0.29
ClinPred		0.33	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.60
Mutation Taster		=91/9	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: rs752980022; hg19: chr3-38049753; COSMIC: COSV52184072; COSMIC: COSV52184072;