12-67312686-G-A

Variant names:

• chr12-67312686-G-A
• rs1060350
• NM_018448.5:c.3549G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018448.5(CAND1):​c.3549G>A​(p.Leu1183Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,612,692 control chromosomes in the GnomAD database, including 260,499 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 0.48 (19270 hom., cov: 32)
  • Exomes 𝑓: 0.57 (241229 hom.)
• Consequence: CAND1 NM_018448.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.843
• Publications: 23 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018448.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAND1	NM_018448.5	MANE Select	c.3549G>A	p.Leu1183Leu	synonymous	Exon 15 of 15	NP_060918.2
	CAND1	NM_001329674.2		c.3477G>A	p.Leu1159Leu	synonymous	Exon 16 of 16	NP_001316603.1
	CAND1	NM_001329675.2		c.3477G>A	p.Leu1159Leu	synonymous	Exon 16 of 16	NP_001316604.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAND1	ENST00000545606.6	TSL:1 MANE Select	c.3549G>A	p.Leu1183Leu	synonymous	Exon 15 of 15	ENSP00000442318.1
	CAND1	ENST00000544619.1	TSL:1	c.2169G>A	p.Leu723Leu	synonymous	Exon 9 of 9	ENSP00000444089.1

Frequencies

GnomAD3 genomes AF: 0.484 AC: 73411 AN: 151812 Hom.: 19251 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.505

GnomAD2 exomes AF: 0.522 AC: 130604 AN: 250100 AF XY: 0.529

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.500

Gnomad ASJ exome AF: 0.530

Gnomad EAS exome AF: 0.345

Gnomad FIN exome AF: 0.538

Gnomad NFE exome AF: 0.590

Gnomad OTH exome AF: 0.538

GnomAD4 exome AF: 0.570 AC: 832364 AN: 1460762 Hom.: 241229 Cov.: 38 AF XY: 0.569 AC XY: 413758 AN XY: 726728

African (AFR) AF: 0.274 AC: 9153 AN: 33446

American (AMR) AF: 0.500 AC: 22327 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 13799 AN: 26110

East Asian (EAS) AF: 0.315 AC: 12486 AN: 39676

South Asian (SAS) AF: 0.521 AC: 44940 AN: 86180

European-Finnish (FIN) AF: 0.534 AC: 28514 AN: 53356

Middle Eastern (MID) AF: 0.535 AC: 3085 AN: 5766

European-Non Finnish (NFE) AF: 0.598 AC: 664741 AN: 1111226

Other (OTH) AF: 0.552 AC: 33319 AN: 60346

GnomAD4 genome AF: 0.483 AC: 73447 AN: 151930 Hom.: 19270 Cov.: 32 AF XY: 0.482 AC XY: 35788 AN XY: 74202

African (AFR) AF: 0.279 AC: 11583 AN: 41468

American (AMR) AF: 0.526 AC: 8023 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 1800 AN: 3468

East Asian (EAS) AF: 0.341 AC: 1760 AN: 5166

South Asian (SAS) AF: 0.519 AC: 2499 AN: 4814

European-Finnish (FIN) AF: 0.539 AC: 5681 AN: 10532

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.594 AC: 40349 AN: 67916

Other (OTH) AF: 0.511 AC: 1079 AN: 2110

Alfa AF: 0.565 Hom.: 48915

Bravo AF: 0.468

Asia WGS AF: 0.445 AC: 1544 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.7
DANN	Benign	0.70
PhyloP100		0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1060350; hg19: chr12-67706466; COSMIC: COSV73389559; COSMIC: COSV73389559;