17-79784771-G-C

Variant names:

• chr17-79784771-G-C
• rs121908256
• NM_005189.3:c.1328G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_005189.3(CBX2):​c.1328G>C​(p.Arg443Pro) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CBX2 NM_005189.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.714

Genes affected

CBX2 (HGNC:1552): (chromobox 2) This gene encodes a component of the polycomb multiprotein complex, which is required to maintain the transcriptionally repressive state of many genes throughout development via chromatin remodeling and modification of histones. Disruption of this gene in mice results in male-to-female gonadal sex reversal. Mutations in this gene are also associated with gonadal dysgenesis in humans. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-79784771-G-C is Pathogenic according to our data. Variant chr17-79784771-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 6827.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20079765). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBX2	NM_005189.3	c.1328G>C	p.Arg443Pro	missense_variant	Exon 5 of 5	ENST00000310942.9	NP_005180.1
CBX2	XM_011525382.2	c.1328G>C	p.Arg443Pro	missense_variant	Exon 5 of 6		XP_011523684.1
CBX2	XM_011525383.3	c.1073G>C	p.Arg358Pro	missense_variant	Exon 5 of 6		XP_011523685.1
CBX2	XM_047436946.1	c.1073G>C	p.Arg358Pro	missense_variant	Exon 4 of 5		XP_047292902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBX2	ENST00000310942.9	c.1328G>C	p.Arg443Pro	missense_variant	Exon 5 of 5	1	NM_005189.3	ENSP00000308750.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

46,XY sex reversal 5 Pathogenic:1 Other:1

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.89
DANN	Benign	0.60
DEOGEN2	Benign	0.092	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.038
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.058
MutPred		0.20		Loss of MoRF binding (P = 0.0199);
MVP		0.10
MPC		0.048
ClinPred		0.16	T
GERP RS		-5.7
Varity_R		0.19
gMVP		0.20

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: rs121908256; hg19: chr17-77758570;