17-38735309-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007144.3(PCGF2):c.949A>T(p.Ser317Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,375,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: PCGF2 NM_007144.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0950

Genes affected

PCGF2 (HGNC:12929): (polycomb group ring finger 2) The protein encoded by this gene contains a RING finger motif and is similar to the polycomb group (PcG) gene products. PcG gene products form complexes via protein-protein interaction and maintain the transcription repression of genes involved in embryogenesis, cell cycles, and tumorigenesis. This protein was shown to act as a negative regulator of transcription and has tumor suppressor activity. The expression of this gene was detected in various tumor cells, but is limited in neural organs in normal tissues. Knockout studies in mice suggested that this protein may negatively regulate the expression of different cytokines, chemokines, and chemokine receptors, and thus plays an important role in lymphocyte differentiation and migration, as well as in immune responses. [provided by RefSeq, Jul 2008]

CISD3 (HGNC:27578): (CDGSH iron sulfur domain 3) CISD3 is a member of the CDGSH domain-containing family, which may play a role in regulating electron transport and oxidative phosphorylation (Wiley et al., 2007 [PubMed 17376863]).[supplied by OMIM, Apr 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059627265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCGF2	NM_007144.3	c.949A>T	p.Ser317Cys	missense_variant	11/11	ENST00000620225.5
CISD3	NM_001136498.2	c.*1854T>A		3_prime_UTR_variant	4/4	ENST00000613478.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCGF2	ENST00000620225.5	c.949A>T	p.Ser317Cys	missense_variant	11/11	1	NM_007144.3	P1
CISD3	ENST00000613478.2	c.*1854T>A		3_prime_UTR_variant	4/4	2	NM_001136498.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000650 AC: 1 AN: 153910 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 80346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000385

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000145 AC: 2 AN: 1375492 Hom.: 0 Cov.: 33 AF XY: 0.00000149 AC XY: 1 AN XY: 673360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000273

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.41e-7

Gnomad4 OTH exome AF: 0.00

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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 05, 2022

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 317 of the PCGF2 protein (p.Ser317Cys). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with PCGF2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	16
Dann	Benign	0.93
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.44	N
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L
MutationTaster	Benign	1.0	D;D;D;N;N;N
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.094	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.054
MutPred		0.26		Loss of glycosylation at S317 (P = 0.0191);Loss of glycosylation at S317 (P = 0.0191);Loss of glycosylation at S317 (P = 0.0191);
MVP		0.28
ClinPred		0.16	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.27

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: rs1298823443; hg19: chr17-36891562;