chr12-67298969-C-T

Variant names:

• chr12-67298969-C-T
• rs758242738
• NM_018448.5:c.874C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018448.5(CAND1):​c.874C>T​(p.Pro292Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,380,690 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CAND1 NM_018448.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3869247).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAND1	NM_018448.5	MANE Select	c.874C>T	p.Pro292Ser	missense	Exon 7 of 15	NP_060918.2
	CAND1	NM_001329674.2		c.802C>T	p.Pro268Ser	missense	Exon 8 of 16	NP_001316603.1
	CAND1	NM_001329675.2		c.802C>T	p.Pro268Ser	missense	Exon 8 of 16	NP_001316604.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAND1	ENST00000545606.6	TSL:1 MANE Select	c.874C>T	p.Pro292Ser	missense	Exon 7 of 15	ENSP00000442318.1	Q86VP6-1
	CAND1	ENST00000909423.1		c.874C>T	p.Pro292Ser	missense	Exon 7 of 14	ENSP00000579482.1
	CAND1	ENST00000540319.5	TSL:2	n.520C>T		non_coding_transcript_exon	Exon 4 of 10	ENSP00000445794.1	H0YH27

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248140 AF XY: 0.00

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 FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1380690 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 690590

⚠️ 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: 31600

American (AMR) AF: 0.00 AC: 0 AN: 43922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25540

East Asian (EAS) AF: 0.00 AC: 0 AN: 39064

South Asian (SAS) AF: 0.00 AC: 0 AN: 83630

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.00000288 AC: 3 AN: 1040774

Other (OTH) AF: 0.00 AC: 0 AN: 57578

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000316713), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.35
Sift	Benign	0.10	T
Sift4G	Benign	0.17	T
Polyphen		0.13	B
Vest4		0.57
MutPred		0.51		Gain of catalytic residue at T296 (P = 0.0019)
MVP		0.80
MPC		0.59
ClinPred		0.56	D
GERP RS		5.6
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.48
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs758242738; hg19: chr12-67692749;