12-67304671-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018448.5(CAND1):c.1360T>G(p.Cys454Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CAND1
NM_018448.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.24

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAND1	NM_018448.5 link	c.1360T>G	p.Cys454Gly	missense_variant	Exon 9 of 15	ENST00000545606.6	NP_060918.2	Q86VP6-1
CAND1	NM_001329674.2 link	c.1288T>G	p.Cys430Gly	missense_variant	Exon 10 of 16		NP_001316603.1
CAND1	NM_001329675.2 link	c.1288T>G	p.Cys430Gly	missense_variant	Exon 10 of 16		NP_001316604.1
CAND1	NM_001329676.2 link	c.1261T>G	p.Cys421Gly	missense_variant	Exon 10 of 16		NP_001316605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAND1	ENST00000545606.6 link	c.1360T>G	p.Cys454Gly	missense_variant	Exon 9 of 15	1	NM_018448.5	ENSP00000442318.1	Q86VP6-1
CAND1	ENST00000544619.1 link	c.484T>G	p.Cys162Gly	missense_variant	Exon 3 of 9	1		ENSP00000444089.1	A0A0C4DGH5
CAND1	ENST00000540319.5 link	n.1006T>G		non_coding_transcript_exon_variant	Exon 6 of 10	2		ENSP00000445794.1	H0YH27

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251156

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461638

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1360T>G (p.C454G) alteration is located in exon 9 (coding exon 9) of the CAND1 gene. This alteration results from a T to G substitution at nucleotide position 1360, causing the cysteine (C) at amino acid position 454 to be replaced by a glycine (G). 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

0.63

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Uncertain

0.43

T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.8

L;.

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-10

D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0040

D;T

Sift4G

Benign

0.12

T;D

Polyphen

0.75

P;.

Vest4

0.86

MutPred

0.70

Loss of helix (P = 0.028);.;

MVP

0.94

MPC

1.7

ClinPred

0.99

GERP RS

6.0

Varity_R

0.91

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over