12-67304737-C-T

Variant names:

• chr12-67304737-C-T
• rs1175591077
• NM_018448.5:c.1426C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018448.5(CAND1):​c.1426C>T​(p.Leu476Phe) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAND1 NM_018448.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAND1	NM_018448.5	c.1426C>T	p.Leu476Phe	missense_variant	Exon 9 of 15	ENST00000545606.6	NP_060918.2
CAND1	NM_001329674.2	c.1354C>T	p.Leu452Phe	missense_variant	Exon 10 of 16		NP_001316603.1
CAND1	NM_001329675.2	c.1354C>T	p.Leu452Phe	missense_variant	Exon 10 of 16		NP_001316604.1
CAND1	NM_001329676.2	c.1327C>T	p.Leu443Phe	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.1426C>T	p.Leu476Phe	missense_variant	Exon 9 of 15	1	NM_018448.5	ENSP00000442318.1
CAND1	ENST00000544619.1	c.494+56C>T		intron_variant	Intron 3 of 8	1		ENSP00000444089.1
CAND1	ENST00000540319.5	n.1072C>T		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

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1426C>T (p.L476F) alteration is located in exon 9 (coding exon 9) of the CAND1 gene. This alteration results from a C to T substitution at nucleotide position 1426, causing the leucine (L) at amino acid position 476 to be replaced by a phenylalanine (F). 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	0.75
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.61		Gain of catalytic residue at P474 (P = 0.0457);
MVP		0.86
MPC		1.6
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.70
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1175591077; hg19: chr12-67698517;