NM_002661.5:c.1934C>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002661.5(PLCG2):c.1934C>A(p.Pro645Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,778 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P645L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PLCG2
NM_002661.5 missense, splice_region

Scores

Splicing: ADA: 0.01273

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.42

Publications

0 publications found

Variant links:

Genes affected

PLCG2 (HGNC:9066): (phospholipase C gamma 2) The protein encoded by this gene is a transmembrane signaling enzyme that catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate to 1D-myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) using calcium as a cofactor. IP3 and DAG are second messenger molecules important for transmitting signals from growth factor receptors and immune system receptors across the cell membrane. Mutations in this gene have been found in autoinflammation, antibody deficiency, and immune dysregulation syndrome and familial cold autoinflammatory syndrome 3. [provided by RefSeq, Mar 2014]

PLCG2 Gene-Disease associations (from GenCC):

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
familial cold autoinflammatory syndrome 3
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

PLCG2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002661.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCG2	NM_002661.5	MANE Select	c.1934C>A	p.Pro645Gln	missense splice_region	Exon 18 of 33	NP_002652.2	P16885
PLCG2	NM_001425749.1		c.1934C>A	p.Pro645Gln	missense splice_region	Exon 19 of 34	NP_001412678.1	P16885
PLCG2	NM_001425750.1		c.1934C>A	p.Pro645Gln	missense splice_region	Exon 18 of 33	NP_001412679.1	P16885

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.1934C>A	p.Pro645Gln	missense splice_region	Exon 18 of 33	ENSP00000482457.1	P16885
PLCG2	ENST00000567980.5	TSL:1	n.2178C>A		splice_region non_coding_transcript_exon	Exon 17 of 20
PLCG2	ENST00000902427.1		c.2087C>A	p.Pro696Gln	missense splice_region	Exon 19 of 34	ENSP00000572486.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1454778

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724128

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111786

Other (OTH)

AF:

0.0000166

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.30

Eigen

Benign

-0.019

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.43

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.7

PhyloP100

3.4

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.76

REVEL

Uncertain

0.32

Sift

Benign

0.066

Sift4G

Benign

0.14

Polyphen

0.083

Vest4

0.36

MutPred

0.32

Loss of catalytic residue at W646 (P = 0.0612)

MVP

0.76

MPC

0.34

ClinPred

0.57

GERP RS

5.0

Varity_R

0.089

gMVP

0.42

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.013

dbscSNV1_RF

Benign

0.27

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over