chr2-198084292-A-T

Position:

• chr2-198084292-A-T

Variant summary

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

The NM_006226.4(PLCL1):​c.775A>T​(p.Met259Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: PLCL1 NM_006226.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

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=0.075694084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCL1	NM_006226.4	c.775A>T	p.Met259Leu	missense_variant	2/6	ENST00000428675.6
PLCL1	XM_005246643.5	c.553A>T	p.Met185Leu	missense_variant	2/6
PLCL1	XM_005246644.5	c.538A>T	p.Met180Leu	missense_variant	2/6
PLCL1	XM_017004339.3	c.538A>T	p.Met180Leu	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCL1	ENST00000428675.6	c.775A>T	p.Met259Leu	missense_variant	2/6	1	NM_006226.4	P1
PLCL1	ENST00000487695.6	c.553A>T	p.Met185Leu	missense_variant	2/6	5
PLCL1	ENST00000435320.1	c.*547A>T		3_prime_UTR_variant, NMD_transcript_variant	3/7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Sep 12, 2023

The c.775A>T (p.M259L) alteration is located in exon 2 (coding exon 2) of the PLCL1 gene. This alteration results from a A to T substitution at nucleotide position 775, causing the methionine (M) at amino acid position 259 to be replaced by a leucine (L). 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	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.69
DEOGEN2	Benign	0.037	T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.076	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.80	N;N;.
REVEL	Benign	0.075
Sift	Benign	0.88	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.21
MutPred		0.47		Loss of catalytic residue at M259 (P = 0.0923);.;.;
MVP		0.085
MPC		0.30
ClinPred		0.71	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.38

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: chr2-198949016;