dbSNP rs773612198: CDC40:p.Arg323Cys (chr6-110215310-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_015891.3(CDC40):c.967C>T(p.Arg323Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CDC40
NM_015891.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.86

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC40	NM_015891.3 link	c.967C>T	p.Arg323Cys	missense_variant	Exon 9 of 15	ENST00000307731.2	NP_056975.1	O60508
CDC40	XM_047418862.1 link	c.232C>T	p.Arg78Cys	missense_variant	Exon 7 of 13		XP_047274818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDC40	ENST00000307731.2 link	c.967C>T	p.Arg323Cys	missense_variant	Exon 9 of 15	1	NM_015891.3	ENSP00000304370.1	O60508
CDC40	ENST00000368932.5 link	c.967C>T	p.Arg323Cys	missense_variant	Exon 10 of 16	5		ENSP00000357928.1	O60508
CDC40	ENST00000368930.5 link	c.967C>T	p.Arg323Cys	missense_variant	Exon 9 of 15	2		ENSP00000357926.1	Q5SRN1
CDC40	ENST00000606893.5 link	n.2397C>T		non_coding_transcript_exon_variant	Exon 9 of 15	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251358

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461006

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726884

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152010

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.967C>T (p.R323C) alteration is located in exon 9 (coding exon 9) of the CDC40 gene. This alteration results from a C to T substitution at nucleotide position 967, causing the arginine (R) at amino acid position 323 to be replaced by a cysteine (C). 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

0.22

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

T;T;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.9

L;L;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.0

D;D;D

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.84

MutPred

0.59

Loss of MoRF binding (P = 0.0229);Loss of MoRF binding (P = 0.0229);Loss of MoRF binding (P = 0.0229);

MVP

0.74

MPC

2.0

ClinPred

0.99

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.53

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over