Genetic Variant CAND1:p.Thr32Met (chr12-67281936-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001329676.2(CAND1):c.-115C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000124 in 1,454,926 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CAND1
NM_001329676.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.85

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25177556).

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAND1	NM_018448.5 link	c.95C>T	p.Thr32Met	missense_variant	Exon 2 of 15	ENST00000545606.6	NP_060918.2	Q86VP6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAND1	ENST00000545606.6 link	c.95C>T	p.Thr32Met	missense_variant	Exon 2 of 15	1	NM_018448.5	ENSP00000442318.1	Q86VP6-1
CAND1	ENST00000540525.1 link	c.23C>T	p.Thr8Met	missense_variant	Exon 2 of 3	4		ENSP00000437594.1	F5H6I6
CAND1	ENST00000539434.1 link	n.87C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2
CAND1	ENST00000541058.1 link	n.423C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000243

AC:

AN:

246444

Hom.:

AF XY:

0.0000225

AC XY:

AN XY:

133336

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000937

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1454926

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

723906

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000507

Gnomad4 SAS exome

AF:

0.0000353

Gnomad4 FIN exome

AF:

0.0000565

Gnomad4 NFE exome

AF:

0.00000812

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.95C>T (p.T32M) alteration is located in exon 2 (coding exon 2) of the CAND1 gene. This alteration results from a C to T substitution at nucleotide position 95, causing the threonine (T) at amino acid position 32 to be replaced by a methionine (M). 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

0.077

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

0.023

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.97

L;.

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.16

Sift

Benign

0.24

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0050

B;.

Vest4

0.24

MVP

0.72

MPC

1.9

ClinPred

0.18

GERP RS

5.9

Varity_R

0.20

gMVP

0.43

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

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