1-33354433-G-C

Variant names:

• chr1-33354433-G-C
• rs150120585
• NM_001385109.1:c.1526C>G

Variant summary

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

The NM_001385109.1(PHC2):​c.1526C>G​(p.Thr509Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. T509M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PHC2 NM_001385109.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.692
• Publications: 0 publications found

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

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=0.057304412).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385109.1. 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
	PHC2	NM_001385109.1	MANE Select	c.1526C>G	p.Thr509Arg	missense	Exon 9 of 15	NP_001372038.1	Q8IXK0-5
	PHC2	NM_001385112.1		c.1592C>G	p.Thr531Arg	missense	Exon 9 of 15	NP_001372041.1	A0A994J5J9
	PHC2	NM_001385119.1		c.1526C>G	p.Thr509Arg	missense	Exon 10 of 16	NP_001372048.1	Q8IXK0-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHC2	ENST00000683057.1	MANE Select	c.1526C>G	p.Thr509Arg	missense	Exon 9 of 15	ENSP00000507877.1	Q8IXK0-5
	PHC2	ENST00000257118.5	TSL:1	c.1523C>G	p.Thr508Arg	missense	Exon 8 of 14	ENSP00000257118.5	Q8IXK0-1
	PHC2	ENST00000431992.6	TSL:1	c.1439C>G	p.Thr480Arg	missense	Exon 8 of 14	ENSP00000389436.2	A0A0A0MSI2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251074 AF XY: 0.00000737

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461612 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74346

African (AFR) AF: 0.000169 AC: 7 AN: 41440

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.69
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.022
Sift	Benign	0.19	T
Sift4G	Benign	0.15	T
Polyphen		0.072	B
Vest4		0.18
MVP		0.38
MPC		0.55
ClinPred		0.018	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.081
gMVP		0.28
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150120585; hg19: chr1-33820034;