1-2476610-C-T

Variant names:

• chr1-2476610-C-T
• rs1570395737
• NM_014638.4:c.22C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014638.4(PLCH2):​c.22C>T​(p.Pro8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,432,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLCH2 NM_014638.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.105
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060697526).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014638.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCH2	NM_014638.4	MANE Select	c.22C>T	p.Pro8Ser	missense	Exon 1 of 22	NP_055453.2
	PLCH2	NM_001303013.1		c.-911C>T		5_prime_UTR	Exon 1 of 22	NP_001289942.1	O75038
	PLCH2	NM_001303012.2		c.44-1866C>T		intron	N/A	NP_001289941.1	O75038-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCH2	ENST00000378486.8	TSL:1 MANE Select	c.22C>T	p.Pro8Ser	missense	Exon 1 of 22	ENSP00000367747.3	O75038-1
	PLCH2	ENST00000419816.6	TSL:5	c.22C>T	p.Pro8Ser	missense	Exon 1 of 22	ENSP00000389803.2	O75038-1
	PLCH2	ENST00000449969.5	TSL:5	c.44-1866C>T		intron	N/A	ENSP00000397289.1	O75038-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1432986 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 711086

African (AFR) AF: 0.00 AC: 0 AN: 32978

American (AMR) AF: 0.00 AC: 0 AN: 40534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25476

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38390

South Asian (SAS) AF: 0.00 AC: 0 AN: 82898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5020

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100474

Other (OTH) AF: 0.0000168 AC: 1 AN: 59354

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.2
DANN	Benign	0.67
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.10
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.0090
Sift	Benign	0.042	D
Sift4G	Benign	0.12	T
Polyphen		0.0080	B
Vest4		0.15
MutPred		0.16		Loss of catalytic residue at P8 (P = 0.0055)
MVP		0.17
ClinPred		0.20	T
GERP RS		-3.3
PromoterAI		-0.058	Neutral
Varity_R		0.033
gMVP		0.16
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1570395737; hg19: chr1-2408049;