1-2476671-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014638.4(PLCH2):c.83G>C(p.Gly28Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,610,838 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (15 hom., cov: 34)
  • Exomes 𝑓: 0.0023 (132 hom.)
• Consequence: PLCH2 NM_014638.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.53

Genes affected

PLCH2 (HGNC:29037): (phospholipase C eta 2) PLCH2 is a member of the PLC-eta family of the phosphoinositide-specific phospholipase C (PLC) superfamily of enzymes that cleave PtdIns(4,5) P2 to generate second messengers inositol 1,4,5-trisphosphate and diacylglycerol (Zhou et al., 2005 [PubMed 16107206]).[supplied by OMIM, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002139032).
• BP6: Variant 1-2476671-G-C is Benign according to our data. Variant chr1-2476671-G-C is described in ClinVar as [Benign]. Clinvar id is 779852.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCH2	NM_014638.4	c.83G>C	p.Gly28Ala	missense_variant	1/22	ENST00000378486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCH2	ENST00000378486.8	c.83G>C	p.Gly28Ala	missense_variant	1/22	1	NM_014638.4	P2
PLCH2	ENST00000419816.6	c.83G>C	p.Gly28Ala	missense_variant	1/22	5		P2
PLCH2	ENST00000449969.5	c.44-1805G>C		intron_variant		5		A2
PLCH2	ENST00000609981.5	c.116-1805G>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152200 Hom.: 15 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0632

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00468 AC: 1136 AN: 242944 Hom.: 29 AF XY: 0.00429 AC XY: 569 AN XY: 132528

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0622

Gnomad SAS exome AF: 0.000594

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000364

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.00227 AC: 3312 AN: 1458520 Hom.: 132 Cov.: 31 AF XY: 0.00220 AC XY: 1599 AN XY: 725442

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0765

Gnomad4 SAS exome AF: 0.000570

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.00309

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152318 Hom.: 15 Cov.: 34 AF XY: 0.00248 AC XY: 185 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0630

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.0000716 Hom.: 0

Bravo AF: 0.00235

ExAC AF: 0.00468 AC: 562

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000596

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	16
Dann	Benign	0.86
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.85	D
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.75	N;N
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.45	T
Sift4G	Benign	0.12	T;T
Polyphen		0.058	B;B
Vest4		0.23
MVP		0.38
ClinPred		0.040	T
GERP RS		2.7
Varity_R		0.069
gMVP		0.26

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: rs79733537; hg19: chr1-2408110; COSMIC: COSV53945824; COSMIC: COSV53945824;