rs7976686

chr12-67294938-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018448.5(CAND1):c.368-95G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0857 in 1,294,540 control chromosomes in the GnomAD database, including 11,454 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (5663 hom., cov: 33)
  • Exomes 𝑓: 0.072 (5791 hom.)
• Consequence: CAND1 NM_018448.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.305

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAND1	NM_018448.5	c.368-95G>A		intron_variant		ENST00000545606.6
CAND1	NM_001329674.2	c.296-95G>A		intron_variant
CAND1	NM_001329675.2	c.296-95G>A		intron_variant
CAND1	NM_001329676.2	c.269-95G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAND1	ENST00000545606.6	c.368-95G>A		intron_variant		1	NM_018448.5	P1
CAND1	ENST00000535146.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28773 AN: 152106 Hom.: 5637 Cov.: 33

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0896

Gnomad SAS AF: 0.0521

Gnomad FIN AF: 0.0466

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0642

Gnomad OTH AF: 0.156

GnomAD4 exome AF: 0.0718 AC: 82062 AN: 1142316 Hom.: 5791 Cov.: 13 AF XY: 0.0696 AC XY: 39838 AN XY: 572364

Gnomad4 AFR exome AF: 0.506

Gnomad4 AMR exome AF: 0.0663

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.0684

Gnomad4 SAS exome AF: 0.0428

Gnomad4 FIN exome AF: 0.0471

Gnomad4 NFE exome AF: 0.0606

Gnomad4 OTH exome AF: 0.0935

GnomAD4 genome AF: 0.189 AC: 28841 AN: 152224 Hom.: 5663 Cov.: 33 AF XY: 0.183 AC XY: 13658 AN XY: 74450

Gnomad4 AFR AF: 0.502

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.0898

Gnomad4 SAS AF: 0.0513

Gnomad4 FIN AF: 0.0466

Gnomad4 NFE AF: 0.0642

Gnomad4 OTH AF: 0.154

Alfa AF: 0.0842 Hom.: 1693

Bravo AF: 0.210

Asia WGS AF: 0.0870 AC: 302 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	5.1
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs7976686; hg19: chr12-67688718; COSMIC: COSV73338537; COSMIC: COSV73338537;