Variant 12-67305350-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000545606.6(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. 13/21 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
ENST00000545606.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.79

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2109614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CAND1	NM_018448.5 linkuse as main transcript	c.1682C>T	p.Ala561Val	missense_variant	10/15	ENST00000545606.6	NP_060918.2
CAND1	NM_001329674.2 linkuse as main transcript	c.1610C>T	p.Ala537Val	missense_variant	11/16		NP_001316603.1
CAND1	NM_001329675.2 linkuse as main transcript	c.1610C>T	p.Ala537Val	missense_variant	11/16		NP_001316604.1
CAND1	NM_001329676.2 linkuse as main transcript	c.1583C>T	p.Ala528Val	missense_variant	11/16		NP_001316605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAND1	ENST00000545606.6 linkuse as main transcript	c.1682C>T	p.Ala561Val	missense_variant	10/15	1	NM_018448.5	ENSP00000442318	P1	Q86VP6-1
CAND1	ENST00000544619.1 linkuse as main transcript	c.495-193C>T		intron_variant		1		ENSP00000444089
CAND1	ENST00000540319.5 linkuse as main transcript	c.1290+38C>T		intron_variant, NMD_transcript_variant		2		ENSP00000445794

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.1682C>T (p.A561V) alteration is located in exon 10 (coding exon 10) of the CAND1 gene. This alteration results from a C to T substitution at nucleotide position 1682, causing the alanine (A) at amino acid position 561 to be replaced by a valine (V). 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

0.12

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.32

DEOGEN2

Benign

0.097

Eigen

Benign

0.0044

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.020

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.16

REVEL

Benign

0.17

Sift

Benign

1.0

Sift4G

Benign

0.50

Polyphen

0.0010

Vest4

0.44

MutPred

0.36

Gain of ubiquitination at K566 (P = 0.102);

MVP

0.63

MPC

0.57

ClinPred

0.96

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.40

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over