chr12-67306123-G-A

Variant summary

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

The ENST00000545606.6(CAND1):​c.2455G>A​(p.Gly819Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,972 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: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CAND1
ENST00000545606.6 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.70
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]

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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=0.21169028).
BS2
High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CAND1NM_018448.5 linkuse as main transcriptc.2455G>A p.Gly819Ser missense_variant 10/15 ENST00000545606.6 NP_060918.2
CAND1NM_001329674.2 linkuse as main transcriptc.2383G>A p.Gly795Ser missense_variant 11/16 NP_001316603.1
CAND1NM_001329675.2 linkuse as main transcriptc.2383G>A p.Gly795Ser missense_variant 11/16 NP_001316604.1
CAND1NM_001329676.2 linkuse as main transcriptc.2356G>A p.Gly786Ser missense_variant 11/16 NP_001316605.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CAND1ENST00000545606.6 linkuse as main transcriptc.2455G>A p.Gly819Ser missense_variant 10/151 NM_018448.5 ENSP00000442318 P1Q86VP6-1
CAND1ENST00000544619.1 linkuse as main transcriptc.1075G>A p.Gly359Ser missense_variant 4/91 ENSP00000444089
CAND1ENST00000540319.5 linkuse as main transcriptc.1290+811G>A intron_variant, NMD_transcript_variant 2 ENSP00000445794

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152140
Hom.:
0
Cov.:
32
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250954
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135638
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:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461832
Hom.:
0
Cov.:
34
AF XY:
0.0000220
AC XY:
16
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74310
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000847
Hom.:
0
Bravo
AF:
0.0000151
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

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 submitterclinical testingAmbry GeneticsOct 05, 2023The c.2455G>A (p.G819S) alteration is located in exon 10 (coding exon 10) of the CAND1 gene. This alteration results from a G to A substitution at nucleotide position 2455, causing the glycine (G) at amino acid position 819 to be replaced by a serine (S). 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
0.096
BayesDel_addAF
Uncertain
0.048
T
BayesDel_noAF
Uncertain
-0.060
CADD
Benign
20
DANN
Benign
0.53
DEOGEN2
Benign
0.11
T;T
Eigen
Benign
-0.090
Eigen_PC
Benign
0.19
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.21
T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
-0.97
N;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Benign
1.3
N;N
REVEL
Benign
0.29
Sift
Benign
0.95
T;T
Sift4G
Benign
0.73
T;T
Polyphen
0.0010
B;.
Vest4
0.73
MVP
0.83
MPC
0.57
ClinPred
0.34
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
Varity_R
0.49
gMVP
0.45

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.

Other links and lift over

dbSNP: rs374777050; hg19: chr12-67699903; API