1-2476632-C-T

Variant names:

• chr1-2476632-C-T
• rs777286891
• NM_014638.4:c.44C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001303013.1(PLCH2):​c.-889C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,603,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PLCH2 NM_001303013.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11061162).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303013.1. 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.44C>T	p.Thr15Met	missense	Exon 1 of 22	NP_055453.2
	PLCH2	NM_001303013.1		c.-889C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 22	NP_001289942.1	O75038
	PLCH2	NM_001303013.1		c.-889C>T		5_prime_UTR	Exon 1 of 22	NP_001289942.1	O75038

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCH2	ENST00000378486.8	TSL:1 MANE Select	c.44C>T	p.Thr15Met	missense	Exon 1 of 22	ENSP00000367747.3	O75038-1
	PLCH2	ENST00000419816.6	TSL:5	c.44C>T	p.Thr15Met	missense	Exon 1 of 22	ENSP00000389803.2	O75038-1
	PLCH2	ENST00000449969.5	TSL:5	c.44-1844C>T		intron	N/A	ENSP00000397289.1	O75038-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000647 AC: 15 AN: 231832 AF XY: 0.0000792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000539

Gnomad NFE exome AF: 0.0000572

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000234 AC: 34 AN: 1451540 Hom.: 0 Cov.: 31 AF XY: 0.0000305 AC XY: 22 AN XY: 721394

African (AFR) AF: 0.00 AC: 0 AN: 33322

American (AMR) AF: 0.0000919 AC: 4 AN: 43504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39292

South Asian (SAS) AF: 0.0000942 AC: 8 AN: 84942

European-Finnish (FIN) AF: 0.0000591 AC: 3 AN: 50774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5360

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1108454

Other (OTH) AF: 0.0000333 AC: 2 AN: 59974

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74354

African (AFR) AF: 0.0000482 AC: 2 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000332 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000917 AC: 11

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	0.098
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.067	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.054
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.025	D
Polyphen		0.98	D
Vest4		0.11
MVP		0.35
ClinPred		0.22	T
GERP RS		2.1
PromoterAI		0.0094	Neutral
Varity_R		0.068
gMVP		0.29
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs777286891; hg19: chr1-2408071;