12-67304660-C-A

Variant names:

• chr12-67304660-C-A
• NM_018448.5:c.1349C>A

Variant summary

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

The NM_018448.5(CAND1):​c.1349C>A​(p.Thr450Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAND1 NM_018448.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

Genes affected

CAND1 (HGNC:30688): (cullin associated and neddylation dissociated 1) This gene encodes an essential regulator of Cullin-RING ubiquitin ligases, which are in involved in ubiquitinylation of proteins degraded by the Ub proteasome system. The encoded protein binds to unneddylated cullin-RING box protein complexes and acts as an inhibitor of cullin neddylation and of Skp1, cullin, and F box ubiquitin ligase complex assembly and activity. In mammalian cell culture, this protein predominantly localizes to the cytoplasm. Knockdown of this gene in preadipocytes results in blocked adipogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAND1	NM_018448.5	c.1349C>A	p.Thr450Asn	missense_variant	Exon 9 of 15	ENST00000545606.6	NP_060918.2
CAND1	NM_001329674.2	c.1277C>A	p.Thr426Asn	missense_variant	Exon 10 of 16		NP_001316603.1
CAND1	NM_001329675.2	c.1277C>A	p.Thr426Asn	missense_variant	Exon 10 of 16		NP_001316604.1
CAND1	NM_001329676.2	c.1250C>A	p.Thr417Asn	missense_variant	Exon 10 of 16		NP_001316605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAND1	ENST00000545606.6	c.1349C>A	p.Thr450Asn	missense_variant	Exon 9 of 15	1	NM_018448.5	ENSP00000442318.1
CAND1	ENST00000544619.1	c.473C>A	p.Thr158Asn	missense_variant	Exon 3 of 9	1		ENSP00000444089.1
CAND1	ENST00000540319.5	n.995C>A		non_coding_transcript_exon_variant	Exon 6 of 10	2		ENSP00000445794.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1349C>A (p.T450N) alteration is located in exon 9 (coding exon 9) of the CAND1 gene. This alteration results from a C to A substitution at nucleotide position 1349, causing the threonine (T) at amino acid position 450 to be replaced by an asparagine (N). 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	0.90
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0030	D;T
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.41	B;.
Vest4		0.83
MutPred		0.54		Gain of catalytic residue at R451 (P = 0.0721);.;
MVP		0.67
MPC		1.5
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.79
gMVP		0.76

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: chr12-67698440;