chr12-67294938-G-A

Variant names:

• chr12-67294938-G-A
• rs7976686
• NM_018448.5:c.368-95G>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.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
• Publications: 3 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=-0.7).
• 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 rank	MANE	Protein	UniProt
CAND1	NM_018448.5	c.368-95G>A		intron_variant	Intron 3 of 14	ENST00000545606.6	NP_060918.2
CAND1	NM_001329674.2	c.296-95G>A		intron_variant	Intron 4 of 15		NP_001316603.1
CAND1	NM_001329675.2	c.296-95G>A		intron_variant	Intron 4 of 15		NP_001316604.1
CAND1	NM_001329676.2	c.269-95G>A		intron_variant	Intron 4 of 15		NP_001316605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAND1	ENST00000545606.6	c.368-95G>A		intron_variant	Intron 3 of 14	1	NM_018448.5	ENSP00000442318.1
CAND1	ENST00000535146.1	n.-17G>A		upstream_gene_variant		3
CAND1	ENST00000540319.5	n.-82G>A		upstream_gene_variant		2		ENSP00000445794.1

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

African (AFR) AF: 0.506 AC: 13163 AN: 26010

American (AMR) AF: 0.0663 AC: 2208 AN: 33310

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 1990 AN: 19048

East Asian (EAS) AF: 0.0684 AC: 2407 AN: 35204

South Asian (SAS) AF: 0.0428 AC: 2928 AN: 68448

European-Finnish (FIN) AF: 0.0471 AC: 1945 AN: 41324

Middle Eastern (MID) AF: 0.107 AC: 373 AN: 3486

European-Non Finnish (NFE) AF: 0.0606 AC: 52583 AN: 867754

Other (OTH) AF: 0.0935 AC: 4465 AN: 47732

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

African (AFR) AF: 0.502 AC: 20815 AN: 41486

American (AMR) AF: 0.107 AC: 1640 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 401 AN: 3470

East Asian (EAS) AF: 0.0898 AC: 466 AN: 5188

South Asian (SAS) AF: 0.0513 AC: 248 AN: 4830

European-Finnish (FIN) AF: 0.0466 AC: 494 AN: 10612

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0642 AC: 4367 AN: 68020

Other (OTH) AF: 0.154 AC: 325 AN: 2108

Alfa AF: 0.104 Hom.: 7197

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
PhyloP100		-0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7976686; hg19: chr12-67688718; COSMIC: COSV73338537; COSMIC: COSV73338537;