2-198084144-T-A

Position:

• chr2-198084144-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006226.4(PLCL1):​c.627T>A​(p.Asp209Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLCL1 NM_006226.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.228

Genes affected

PLCL1 (HGNC:9063): (phospholipase C like 1 (inactive)) Predicted to enable phospholipase C activity. Predicted to be involved in negative regulation of cold-induced thermogenesis and phosphatidylinositol-mediated signaling. Predicted to act upstream of or within several processes, including gamma-aminobutyric acid signaling pathway; regulation of GABAergic synaptic transmission; and regulation of peptidyl-serine phosphorylation. Predicted to be located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21021563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCL1	NM_006226.4	c.627T>A	p.Asp209Glu	missense_variant	2/6	ENST00000428675.6	NP_006217.3
PLCL1	XM_005246643.5	c.405T>A	p.Asp135Glu	missense_variant	2/6		XP_005246700.1
PLCL1	XM_005246644.5	c.390T>A	p.Asp130Glu	missense_variant	2/6		XP_005246701.1
PLCL1	XM_017004339.3	c.390T>A	p.Asp130Glu	missense_variant	2/6		XP_016859828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCL1	ENST00000428675.6	c.627T>A	p.Asp209Glu	missense_variant	2/6	1	NM_006226.4	ENSP00000402861	P1
PLCL1	ENST00000487695.6	c.405T>A	p.Asp135Glu	missense_variant	2/6	5		ENSP00000457588
PLCL1	ENST00000435320.1	c.*399T>A		3_prime_UTR_variant, NMD_transcript_variant	3/7	2		ENSP00000410488

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 26, 2022

The c.627T>A (p.D209E) alteration is located in exon 2 (coding exon 2) of the PLCL1 gene. This alteration results from a T to A substitution at nucleotide position 627, causing the aspartic acid (D) at amino acid position 209 to be replaced by a glutamic acid (E). 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	0.32
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.71	N;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.92	P;.;.
Vest4		0.67
MutPred		0.45		Gain of sheet (P = 0.0061);.;.;
MVP		0.13
MPC		0.58
ClinPred		0.96	D
GERP RS		-6.5
Varity_R		0.18
gMVP		0.43

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: rs1692792468; hg19: chr2-198948868;