rs193921038

Variant names:

• chr12-67297652-G-A
• rs193921038
• NM_018448.5:c.737G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018448.5(CAND1):​c.737G>A​(p.Gly246Asp) 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAND1 NM_018448.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 10.0
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAND1	NM_018448.5	c.737G>A	p.Gly246Asp	missense_variant	Exon 5 of 15	ENST00000545606.6	NP_060918.2
CAND1	NM_001329674.2	c.665G>A	p.Gly222Asp	missense_variant	Exon 6 of 16		NP_001316603.1
CAND1	NM_001329675.2	c.665G>A	p.Gly222Asp	missense_variant	Exon 6 of 16		NP_001316604.1
CAND1	NM_001329676.2	c.638G>A	p.Gly213Asp	missense_variant	Exon 6 of 16		NP_001316605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAND1	ENST00000545606.6	c.737G>A	p.Gly246Asp	missense_variant	Exon 5 of 15	1	NM_018448.5	ENSP00000442318.1
CAND1	ENST00000535146.1	n.448G>A		non_coding_transcript_exon_variant	Exon 2 of 3	3
CAND1	ENST00000540319.5	n.383G>A		non_coding_transcript_exon_variant	Exon 2 of 10	2		ENSP00000445794.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Prostate cancer Uncertain:1

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Science for Life laboratory, Karolinska Institutet

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		10
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.66		Gain of catalytic residue at A245 (P = 0.0025);
MVP		0.88
MPC		1.8
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.88
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs193921038; hg19: chr12-67691432; COSMIC: COSV73338589; COSMIC: COSV73338589;