Genetic Variant CAND1:p.Cys453Phe (chr12-67304669-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_018448.5(CAND1):c.1358G>T(p.Cys453Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C453Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CAND1
NM_018448.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.97

Publications

0 publications found

Variant links:

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]

CAND1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CAND1	NM_018448.5	MANE Select	c.1358G>T	p.Cys453Phe	missense	Exon 9 of 15	NP_060918.2
CAND1	NM_001329674.2		c.1286G>T	p.Cys429Phe	missense	Exon 10 of 16	NP_001316603.1
CAND1	NM_001329675.2		c.1286G>T	p.Cys429Phe	missense	Exon 10 of 16	NP_001316604.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CAND1	ENST00000545606.6	TSL:1 MANE Select	c.1358G>T	p.Cys453Phe	missense	Exon 9 of 15	ENSP00000442318.1	Q86VP6-1
CAND1	ENST00000544619.1	TSL:1	c.482G>T	p.Cys161Phe	missense	Exon 3 of 9	ENSP00000444089.1	A0A0C4DGH5
CAND1	ENST00000909423.1		c.1358G>T	p.Cys453Phe	missense	Exon 9 of 14	ENSP00000579482.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461634

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111910

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.085

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.4

PhyloP100

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.39

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

0.94

Vest4

0.83

MutPred

0.50

Gain of catalytic residue at C453 (P = 0.026)

MVP

0.94

MPC

0.99

ClinPred

0.92

GERP RS

6.0

Varity_R

0.71

gMVP

0.68

Mutation Taster

=39/61

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over