6-110217749-C-G

Variant names:

• chr6-110217749-C-G
• NM_015891.3:c.1036C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015891.3(CDC40):​c.1036C>G​(p.Gln346Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC40 NM_015891.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57

Genes affected

CDC40 (HGNC:17350): (cell division cycle 40) Pre-mRNA splicing occurs in two sequential transesterification steps. The protein encoded by this gene is found to be essential for the catalytic step II in pre-mRNA splicing process. It is found in the spliceosome, and contains seven WD repeats, which function in protein-protein interactions. This protein has a sequence similarity to yeast Prp17 protein, which functions in two different cellular processes: pre-mRNA splicing and cell cycle progression. It suggests that this protein may play a role in cell cycle progression. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2627756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC40	NM_015891.3	c.1036C>G	p.Gln346Glu	missense_variant	Exon 10 of 15	ENST00000307731.2	NP_056975.1
CDC40	XM_047418862.1	c.301C>G	p.Gln101Glu	missense_variant	Exon 8 of 13		XP_047274818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC40	ENST00000307731.2	c.1036C>G	p.Gln346Glu	missense_variant	Exon 10 of 15	1	NM_015891.3	ENSP00000304370.1
CDC40	ENST00000368932.5	c.1036C>G	p.Gln346Glu	missense_variant	Exon 11 of 16	5		ENSP00000357928.1
CDC40	ENST00000368930.5	c.1036C>G	p.Gln346Glu	missense_variant	Exon 10 of 15	2		ENSP00000357926.1
CDC40	ENST00000606893.5	n.2466C>G		non_coding_transcript_exon_variant	Exon 10 of 15	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1036C>G (p.Q346E) alteration is located in exon 10 (coding exon 10) of the CDC40 gene. This alteration results from a C to G substitution at nucleotide position 1036, causing the glutamine (Q) at amino acid position 346 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0060	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.073	T;T;T
Eigen	Benign	-0.052
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.24	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.0060	B;B;.
Vest4		0.49
MutPred		0.42		Loss of catalytic residue at Q346 (P = 0.1117);Loss of catalytic residue at Q346 (P = 0.1117);Loss of catalytic residue at Q346 (P = 0.1117);
MVP		0.71
MPC		0.76
ClinPred		0.57	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-110538952;