chr12-67305259-C-A

Position:

• chr12-67305259-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000545606.6(CAND1):​c.1591C>A​(p.Pro531Thr) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAND1 ENST00000545606.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42217225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAND1	NM_018448.5	c.1591C>A	p.Pro531Thr	missense_variant	10/15	ENST00000545606.6	NP_060918.2
CAND1	NM_001329674.2	c.1519C>A	p.Pro507Thr	missense_variant	11/16		NP_001316603.1
CAND1	NM_001329675.2	c.1519C>A	p.Pro507Thr	missense_variant	11/16		NP_001316604.1
CAND1	NM_001329676.2	c.1492C>A	p.Pro498Thr	missense_variant	11/16		NP_001316605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAND1	ENST00000545606.6	c.1591C>A	p.Pro531Thr	missense_variant	10/15	1	NM_018448.5	ENSP00000442318	P1
CAND1	ENST00000544619.1	c.495-284C>A		intron_variant		1		ENSP00000444089
CAND1	ENST00000540319.5	c.1237C>A	p.Pro413Thr	missense_variant, NMD_transcript_variant	7/10	2		ENSP00000445794

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

The c.1591C>A (p.P531T) alteration is located in exon 10 (coding exon 10) of the CAND1 gene. This alteration results from a C to A substitution at nucleotide position 1591, causing the proline (P) at amino acid position 531 to be replaced by a threonine (T). 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	0.25
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.41
Sift	Benign	0.12	T
Sift4G	Benign	0.093	T
Polyphen		0.096	B
Vest4		0.48
MutPred		0.49		Gain of catalytic residue at A526 (P = 0.0014);
MVP		0.84
MPC		1.0
ClinPred		0.87	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.39

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: chr12-67699039;