3-12810321-C-G

Variant names:

• chr3-12810321-C-G
• rs2061841634
• NM_001162499.2:c.754C>G

Variant summary

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

The NM_001162499.2(CAND2):​c.754C>G​(p.Leu252Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,304,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: CAND2 NM_001162499.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10482606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAND2	NM_001162499.2	c.754C>G	p.Leu252Val	missense_variant	Exon 5 of 15	ENST00000456430.6	NP_001155971.1
CAND2	NM_012298.3	c.475C>G	p.Leu159Val	missense_variant	Exon 3 of 13		NP_036430.1
CAND2	XM_011533504.3	c.682C>G	p.Leu228Val	missense_variant	Exon 5 of 15		XP_011531806.1
CAND2	XM_011533503.3	c.754C>G	p.Leu252Val	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.754C>G	p.Leu252Val	missense_variant	Exon 5 of 15	1	NM_001162499.2	ENSP00000387641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1304234 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 636030

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000391

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.754C>G (p.L252V) alteration is located in exon 5 (coding exon 5) of the CAND2 gene. This alteration results from a C to G substitution at nucleotide position 754, causing the leucine (L) at amino acid position 252 to be replaced by a valine (V). 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	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.0089	.;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.14	.;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.12	N;N
REVEL	Benign	0.049
Sift	Benign	0.37	T;T
Sift4G	Benign	0.74	T;T
Polyphen		0.0070	B;B
Vest4		0.17
MutPred		0.47		.;Gain of MoRF binding (P = 0.0951);
MVP		0.39
MPC		1.1
ClinPred		0.16	T
GERP RS		4.2
Varity_R		0.074
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs2061841634; hg19: chr3-12851820;