14-102933818-G-A

Position:

• chr14-102933818-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006035.4(CDC42BPB):​c.5030C>T​(p.Ser1677Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.53

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]

ENSG00000259515 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC42BPB	NM_006035.4	c.5030C>T	p.Ser1677Leu	missense_variant	37/37	ENST00000361246.7	NP_006026.3
CDC42BPB	NM_001411054.1	c.4952C>T	p.Ser1651Leu	missense_variant	36/36		NP_001397983.1
CDC42BPB	XM_005268227.2	c.5081C>T	p.Ser1694Leu	missense_variant	38/38		XP_005268284.1
CDC42BPB	XM_005268228.2	c.5003C>T	p.Ser1668Leu	missense_variant	37/37		XP_005268285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC42BPB	ENST00000361246.7	c.5030C>T	p.Ser1677Leu	missense_variant	37/37	1	NM_006035.4	ENSP00000355237.2
CDC42BPB	ENST00000559043.2	c.4952C>T	p.Ser1651Leu	missense_variant	36/36	5		ENSP00000453384.2
ENSG00000259515	ENST00000560931.1	n.245G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

The c.5030C>T (p.S1677L) alteration is located in exon 37 (coding exon 37) of the CDC42BPB gene. This alteration results from a C to T substitution at nucleotide position 5030, causing the serine (S) at amino acid position 1677 to be replaced by a leucine (L). 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	-0.022	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.4	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.23		Loss of phosphorylation at S1677 (P = 0.0026);
MVP		0.71
MPC		1.2
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.41
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-103400155;