14-102933747-G-C

Position:

chr14-102933747-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2

The NM_006035.4(CDC42BPB):c.5101C>G(p.Leu1701Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,494,710 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

CDC42BPB
NM_006035.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.23

Variant links:

Genes affected

CDC42BPB (HGNC:1738): (CDC42 binding protein kinase beta) This gene encodes a member of the serine/threonine protein kinase family. The encoded protein contains a Cdc42/Rac-binding p21 binding domain resembling that of PAK kinase. The kinase domain of this protein is most closely related to that of myotonic dystrophy kinase-related ROK. Studies of the similar gene in rat suggested that this kinase may act as a downstream effector of Cdc42 in cytoskeletal reorganization. [provided by RefSeq, Jul 2008]

CDC42BPB links:

ENSG00000259515 (HGNC:):

ENSG00000259515 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CDC42BPB. . Gene score misZ 3.6598 (greater than the threshold 3.09). Trascript score misZ 3.9995 (greater than threshold 3.09). GenCC has associacion of gene with Chilton-Okur-Chung neurodevelopmental syndrome, complex neurodevelopmental disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.0548926).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000158 (24/152230) while in subpopulation AFR AF= 0.000481 (20/41540). AF 95% confidence interval is 0.000319. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC42BPB	NM_006035.4 linkuse as main transcript	c.5101C>G	p.Leu1701Val	missense_variant	37/37	ENST00000361246.7	NP_006026.3	Q9Y5S2A0A024R6N2Q86XZ8
CDC42BPB	NM_001411054.1 linkuse as main transcript	c.5023C>G	p.Leu1675Val	missense_variant	36/36		NP_001397983.1
CDC42BPB	XM_005268227.2 linkuse as main transcript	c.5152C>G	p.Leu1718Val	missense_variant	38/38		XP_005268284.1
CDC42BPB	XM_005268228.2 linkuse as main transcript	c.5074C>G	p.Leu1692Val	missense_variant	37/37		XP_005268285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CDC42BPB	ENST00000361246.7 linkuse as main transcript	c.5101C>G	p.Leu1701Val	missense_variant	37/37	1	NM_006035.4	ENSP00000355237.2	Q9Y5S2
CDC42BPB	ENST00000559043.2 linkuse as main transcript	c.5023C>G	p.Leu1675Val	missense_variant	36/36	5		ENSP00000453384.2	H0YLY0
ENSG00000259515	ENST00000560931.1 linkuse as main transcript	n.174G>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000315

AC:

AN:

127124

Hom.:

AF XY:

0.0000563

AC XY:

AN XY:

71064

show subpopulations

Gnomad AFR exome

AF:

0.000404

Gnomad AMR exome

AF:

0.00

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:

0.0000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000283

AC:

AN:

1342480

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

663462

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.000111

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:

0.00000561

Gnomad4 OTH exome

AF:

0.0000360

GnomAD4 genome

AF:

0.000158

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000317

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000334

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.5101C>G (p.L1701V) alteration is located in exon 37 (coding exon 37) of the CDC42BPB gene. This alteration results from a C to G substitution at nucleotide position 5101, causing the leucine (L) at amino acid position 1701 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Chilton-Okur-Chung neurodevelopmental syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.046

Eigen

Benign

0.15

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.75

M_CAP

Benign

0.054

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.7

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.85

REVEL

Benign

0.25

Sift

Uncertain

0.0080

Sift4G

Benign

0.070

Polyphen

0.76

Vest4

0.28

MVP

0.66

MPC

0.47

ClinPred

0.11

GERP RS

3.0

Varity_R

0.060

gMVP

0.39

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