chr1-33354407-C-T

Variant names:

• chr1-33354407-C-T
• rs145232419
• NM_001385109.1:c.1552G>A

Variant summary

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

The NM_001385109.1(PHC2):​c.1552G>A​(p.Ala518Thr) 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. 13/21 in silico tools predict a benign outcome for this variant. 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. A518S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PHC2 NM_001385109.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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]

PHC2-AS1 (HGNC:40205): (PHC2 antisense RNA 1)

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=0.0840908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC2	NM_001385109.1	c.1552G>A	p.Ala518Thr	missense_variant	Exon 9 of 15	ENST00000683057.1	NP_001372038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC2	ENST00000683057.1	c.1552G>A	p.Ala518Thr	missense_variant	Exon 9 of 15		NM_001385109.1	ENSP00000507877.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T;T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.072
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	.;.;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.20	.;N;N
REVEL	Benign	0.053
Sift	Benign	0.19	.;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.045	.;.;B
Vest4		0.17
MutPred		0.17		.;.;Gain of glycosylation at A517 (P = 0.0038);
MVP		0.30
MPC		0.45
ClinPred		0.25	T
GERP RS		3.9
Varity_R		0.044
gMVP		0.30

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: rs145232419; hg19: chr1-33820008;