chr3-12810298-T-G

Variant names:

• chr3-12810298-T-G
• NM_001162499.2:c.731T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001162499.2(CAND2):​c.731T>G​(p.Val244Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CAND2 NM_001162499.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66

Genes affected

CAND2 (HGNC:30689): (cullin associated and neddylation dissociated 2 (putative)) Predicted to enable TBP-class protein binding activity. Predicted to be involved in SCF complex assembly; positive regulation of transcription, DNA-templated; and protein ubiquitination. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAND2	NM_001162499.2	c.731T>G	p.Val244Gly	missense_variant	Exon 5 of 15	ENST00000456430.6	NP_001155971.1
CAND2	NM_012298.3	c.452T>G	p.Val151Gly	missense_variant	Exon 3 of 13		NP_036430.1
CAND2	XM_011533504.3	c.659T>G	p.Val220Gly	missense_variant	Exon 5 of 15		XP_011531806.1
CAND2	XM_011533503.3	c.731T>G	p.Val244Gly	missense_variant	Exon 5 of 14		XP_011531805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAND2	ENST00000456430.6	c.731T>G	p.Val244Gly	missense_variant	Exon 5 of 15	1	NM_001162499.2	ENSP00000387641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 07, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.731T>G (p.V244G) alteration is located in exon 5 (coding exon 5) of the CAND2 gene. This alteration results from a T to G substitution at nucleotide position 731, causing the valine (V) at amino acid position 244 to be replaced by a glycine (G). 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	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	2.0	.;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.69	P;P
Vest4		0.58
MutPred		0.69		.;Gain of disorder (P = 0.0168);
MVP		0.91
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.83
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-12851797;