12-67294938-G-T

Variant names:

• chr12-67294938-G-T
• rs7976686
• NM_018448.5:c.368-95G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018448.5(CAND1):​c.368-95G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000875 in 1,143,240 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: CAND1 NM_018448.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.305
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAND1	NM_018448.5	c.368-95G>T		intron_variant	Intron 3 of 14	ENST00000545606.6	NP_060918.2
CAND1	NM_001329674.2	c.296-95G>T		intron_variant	Intron 4 of 15		NP_001316603.1
CAND1	NM_001329675.2	c.296-95G>T		intron_variant	Intron 4 of 15		NP_001316604.1
CAND1	NM_001329676.2	c.269-95G>T		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>T		intron_variant	Intron 3 of 14	1	NM_018448.5	ENSP00000442318.1
CAND1	ENST00000535146.1	n.-17G>T		upstream_gene_variant		3
CAND1	ENST00000540319.5	n.-82G>T		upstream_gene_variant		2		ENSP00000445794.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.75e-7 AC: 1 AN: 1143240 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 572836

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26110

American (AMR) AF: 0.00 AC: 0 AN: 33342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19078

East Asian (EAS) AF: 0.00 AC: 0 AN: 35218

South Asian (SAS) AF: 0.00 AC: 0 AN: 68496

European-Finnish (FIN) AF: 0.0000242 AC: 1 AN: 41346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3492

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 868378

Other (OTH) AF: 0.00 AC: 0 AN: 47780

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.7
DANN	Benign	0.86
PhyloP100		-0.30

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;