dbSNP rs760430736: CDC40:p.Thr220Arg (chr6-110210735-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_015891.3(CDC40):c.659C>G(p.Thr220Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000701 in 1,425,632 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CDC40
NM_015891.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.48

Variant links:

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]

CDC40 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC40	NM_015891.3 link	c.659C>G	p.Thr220Arg	missense_variant	Exon 6 of 15	ENST00000307731.2	NP_056975.1	O60508
CDC40	XM_047418862.1 link	c.-77C>G		5_prime_UTR_variant	Exon 4 of 13		XP_047274818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDC40	ENST00000307731.2 link	c.659C>G	p.Thr220Arg	missense_variant	Exon 6 of 15	1	NM_015891.3	ENSP00000304370.1	O60508
CDC40	ENST00000368932.5 link	c.659C>G	p.Thr220Arg	missense_variant	Exon 7 of 16	5		ENSP00000357928.1	O60508
CDC40	ENST00000368930.5 link	c.659C>G	p.Thr220Arg	missense_variant	Exon 6 of 15	2		ENSP00000357926.1	Q5SRN1
CDC40	ENST00000606893.5 link	n.760C>G		non_coding_transcript_exon_variant	Exon 7 of 15	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000444

AC:

AN:

224988

Hom.:

AF XY:

0.00000818

AC XY:

AN XY:

122264

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000350

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1425632

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708956

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000258

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.093

T;T;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

.;D;D

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.44

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.91

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.61

T;T;T

Sift4G

Benign

0.67

T;T;T

Polyphen

0.52

P;P;.

Vest4

0.66

MutPred

0.36

Loss of sheet (P = 7e-04);Loss of sheet (P = 7e-04);Loss of sheet (P = 7e-04);

MVP

0.55

MPC

0.86

ClinPred

0.26

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over