chr14-102938137-A-C

Position:

• chr14-102938137-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_006035.4(CDC42BPB):​c.4971T>G​(p.Ser1657Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: CDC42BPB NM_006035.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.155

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CDC42BPB
• BP4: Computational evidence support a benign effect (MetaRNN=0.31139886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC42BPB	NM_006035.4	c.4971T>G	p.Ser1657Arg	missense_variant	36/37	ENST00000361246.7
CDC42BPB	NM_001411054.1	c.4893T>G	p.Ser1631Arg	missense_variant	35/36
CDC42BPB	XM_005268227.2	c.5022T>G	p.Ser1674Arg	missense_variant	37/38
CDC42BPB	XM_005268228.2	c.4944T>G	p.Ser1648Arg	missense_variant	36/37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC42BPB	ENST00000361246.7	c.4971T>G	p.Ser1657Arg	missense_variant	36/37	1	NM_006035.4	P1
CDC42BPB	ENST00000559043.2	c.4893T>G	p.Ser1631Arg	missense_variant	35/36	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 31, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.0074	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.30
Sift	Benign	0.035	D
Sift4G	Uncertain	0.016	D
Polyphen		0.97	D
Vest4		0.36
MutPred		0.13		Loss of phosphorylation at S1657 (P = 0.0062);
MVP		0.64
MPC		0.48
ClinPred		0.97	D
GERP RS		-4.7
Varity_R		0.19
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1026746039; hg19: chr14-103404474;