1-33328917-G-C

Variant names:

• chr1-33328917-G-C
• rs1646429954
• NM_001385109.1:c.2378C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001385109.1(PHC2):​c.2378C>G​(p.Thr793Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHC2 NM_001385109.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.03

Genes affected

PHC2 (HGNC:3183): (polyhomeotic homolog 2) In Drosophila melanogaster, the 'Polycomb' group (PcG) of genes are part of a cellular memory system that is responsible for the stable inheritance of gene activity. PcG proteins form a large multimeric, chromatin-associated protein complex. The protein encoded by this gene has homology to the Drosophila PcG protein 'polyhomeotic' (Ph) and is known to heterodimerize with EDR1 and colocalize with BMI1 in interphase nuclei of human cells. The specific function in human cells has not yet been determined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000225313 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17526871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC2	NM_001385109.1	c.2378C>G	p.Thr793Ser	missense_variant	Exon 14 of 15	ENST00000683057.1	NP_001372038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC2	ENST00000683057.1	c.2378C>G	p.Thr793Ser	missense_variant	Exon 14 of 15		NM_001385109.1	ENSP00000507877.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2375C>G (p.T792S) alteration is located in exon 13 (coding exon 13) of the PHC2 gene. This alteration results from a C to G substitution at nucleotide position 2375, causing the threonine (T) at amino acid position 792 to be replaced by a serine (S). 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	0.10
BayesDel_addAF	Benign	-0.0059	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0065	T;.;T;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.61	T;T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.1	.;.;.;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.11	.;N;N;N
REVEL	Benign	0.28
Sift	Benign	1.0	.;T;T;T
Sift4G	Benign	0.88	T;T;T;T
Polyphen		1.0	.;.;.;D
Vest4		0.21
MutPred		0.35		.;.;.;Gain of relative solvent accessibility (P = 0.0479);
MVP		0.40
MPC		0.49
ClinPred		0.93	D
GERP RS		5.8
Varity_R		0.26
gMVP		0.40

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: rs1646429954; hg19: chr1-33794518;