2-198084322-A-G

Position:

• chr2-198084322-A-G

Variant summary

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

The NM_006226.4(PLCL1):​c.805A>G​(p.Lys269Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLCL1 NM_006226.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41949514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCL1	NM_006226.4	c.805A>G	p.Lys269Glu	missense_variant	2/6	ENST00000428675.6	NP_006217.3
PLCL1	XM_005246643.5	c.583A>G	p.Lys195Glu	missense_variant	2/6		XP_005246700.1
PLCL1	XM_005246644.5	c.568A>G	p.Lys190Glu	missense_variant	2/6		XP_005246701.1
PLCL1	XM_017004339.3	c.568A>G	p.Lys190Glu	missense_variant	2/6		XP_016859828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCL1	ENST00000428675.6	c.805A>G	p.Lys269Glu	missense_variant	2/6	1	NM_006226.4	ENSP00000402861	P1
PLCL1	ENST00000487695.6	c.583A>G	p.Lys195Glu	missense_variant	2/6	5		ENSP00000457588
PLCL1	ENST00000435320.1	c.*577A>G		3_prime_UTR_variant, NMD_transcript_variant	3/7	2		ENSP00000410488

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Aug 05, 2023

The c.805A>G (p.K269E) alteration is located in exon 2 (coding exon 2) of the PLCL1 gene. This alteration results from a A to G substitution at nucleotide position 805, causing the lysine (K) at amino acid position 269 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	Uncertain	0.52
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.4	N;N;.
REVEL	Benign	0.18
Sift	Benign	0.047	D;T;.
Sift4G	Benign	0.17	T;T;T
Polyphen		0.81	P;.;.
Vest4		0.76
MutPred		0.35		Loss of ubiquitination at K269 (P = 0.0309);.;.;
MVP		0.47
MPC		0.74
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.33
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-198949046;