rs752639388

Variant names:

• chr12-67305350-C-T
• rs752639388
• NM_018448.5:c.1682C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-67305350-C-T
• chr12-67305350-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018448.5(CAND1):​c.1682C>T​(p.Ala561Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAND1 NM_018448.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2109614).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018448.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAND1	NM_018448.5	MANE Select	c.1682C>T	p.Ala561Val	missense	Exon 10 of 15	NP_060918.2
	CAND1	NM_001329674.2		c.1610C>T	p.Ala537Val	missense	Exon 11 of 16	NP_001316603.1
	CAND1	NM_001329675.2		c.1610C>T	p.Ala537Val	missense	Exon 11 of 16	NP_001316604.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAND1	ENST00000545606.6	TSL:1 MANE Select	c.1682C>T	p.Ala561Val	missense	Exon 10 of 15	ENSP00000442318.1	Q86VP6-1
	CAND1	ENST00000544619.1	TSL:1	c.495-193C>T		intron	N/A	ENSP00000444089.1	A0A0C4DGH5
	CAND1	ENST00000909423.1		c.1682C>T	p.Ala561Val	missense	Exon 10 of 14	ENSP00000579482.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727194

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111934

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Benign	0.32
DEOGEN2	Benign	0.097	T
Eigen	Benign	0.0044
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	0.50	T
Polyphen		0.0010	B
Vest4		0.44
MutPred		0.36		Gain of ubiquitination at K566 (P = 0.102)
MVP		0.63
MPC		0.57
ClinPred		0.96	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.40
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs752639388; hg19: chr12-67699130;