rs1777162654

Variant names:

• chr6-110180448-T-G
• rs1777162654
• NM_015891.3:c.4T>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015891.3(CDC40):​c.4T>G​(p.Ser2Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,770 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDC40 NM_015891.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.10

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2933994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC40	NM_015891.3	c.4T>G	p.Ser2Ala	missense_variant	Exon 1 of 15	ENST00000307731.2	NP_056975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC40	ENST00000307731.2	c.4T>G	p.Ser2Ala	missense_variant	Exon 1 of 15	1	NM_015891.3	ENSP00000304370.1
CDC40	ENST00000368932.5	c.4T>G	p.Ser2Ala	missense_variant	Exon 2 of 16	5		ENSP00000357928.1
CDC40	ENST00000368930.5	c.4T>G	p.Ser2Ala	missense_variant	Exon 1 of 15	2		ENSP00000357926.1
CDC40	ENST00000606893.5	n.105T>G		non_coding_transcript_exon_variant	Exon 2 of 15	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4T>G (p.S2A) alteration is located in exon 1 (coding exon 1) of the CDC40 gene. This alteration results from a T to G substitution at nucleotide position 4, causing the serine (S) at amino acid position 2 to be replaced by an alanine (A). 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	0.087
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	T;T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.61	.;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L;L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.29	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.84	P;P;.
Vest4		0.49
MutPred		0.20		Loss of glycosylation at S2 (P = 0.0098);Loss of glycosylation at S2 (P = 0.0098);Loss of glycosylation at S2 (P = 0.0098);
MVP		0.65
MPC		0.57
ClinPred		0.87	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.23
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs1777162654; hg19: chr6-110501651;