Variant chr2-198084337-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000428675.6(PLCL1):c.820A>G(p.Thr274Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000576 in 1,613,706 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: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 0 hom. )

Consequence

PLCL1
ENST00000428675.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.74

Variant links:

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]

PLCL1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056174755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PLCL1	NM_006226.4 linkuse as main transcript	c.820A>G	p.Thr274Ala	missense_variant	2/6	ENST00000428675.6	NP_006217.3
PLCL1	XM_005246643.5 linkuse as main transcript	c.598A>G	p.Thr200Ala	missense_variant	2/6		XP_005246700.1
PLCL1	XM_005246644.5 linkuse as main transcript	c.583A>G	p.Thr195Ala	missense_variant	2/6		XP_005246701.1
PLCL1	XM_017004339.3 linkuse as main transcript	c.583A>G	p.Thr195Ala	missense_variant	2/6		XP_016859828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCL1	ENST00000428675.6 linkuse as main transcript	c.820A>G	p.Thr274Ala	missense_variant	2/6	1	NM_006226.4	ENSP00000402861	P1	Q15111-1
PLCL1	ENST00000487695.6 linkuse as main transcript	c.598A>G	p.Thr200Ala	missense_variant	2/6	5		ENSP00000457588
PLCL1	ENST00000435320.1 linkuse as main transcript	c.*592A>G		3_prime_UTR_variant, NMD_transcript_variant	3/7	2		ENSP00000410488

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000255

AC:

AN:

250638

Hom.:

AF XY:

0.000303

AC XY:

AN XY:

135494

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000539

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000604

AC:

883

AN:

1461546

Hom.:

Cov.:

AF XY:

0.000572

AC XY:

416

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000762

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000302

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000354

Hom.:

Bravo

AF:

0.000283

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.820A>G (p.T274A) 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 820, causing the threonine (T) at amino acid position 274 to be replaced by an alanine (A). 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

0.058

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.020

T;T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.0065

MetaRNN

Benign

0.056

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;.;.

MutationTaster

Benign

0.97

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.71

N;N;N

REVEL

Benign

0.062

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.58

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.13

MVP

0.34

MPC

0.31

ClinPred

0.044

GERP RS

4.6

Varity_R

0.064

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over