14-102933737-A-G

Position:

• chr14-102933737-A-G

Variant summary

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

The NM_006035.4(CDC42BPB):​c.5111T>C​(p.Leu1704Pro) variant causes a missense change involving the alteration of a 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDC42BPB NM_006035.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.87

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36104202).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC42BPB	NM_006035.4	c.5111T>C	p.Leu1704Pro	missense_variant	37/37	ENST00000361246.7	NP_006026.3
CDC42BPB	NM_001411054.1	c.5033T>C	p.Leu1678Pro	missense_variant	36/36		NP_001397983.1
CDC42BPB	XM_005268227.2	c.5162T>C	p.Leu1721Pro	missense_variant	38/38		XP_005268284.1
CDC42BPB	XM_005268228.2	c.5084T>C	p.Leu1695Pro	missense_variant	37/37		XP_005268285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC42BPB	ENST00000361246.7	c.5111T>C	p.Leu1704Pro	missense_variant	37/37	1	NM_006035.4	ENSP00000355237.2
CDC42BPB	ENST00000559043.2	c.5033T>C	p.Leu1678Pro	missense_variant	36/36	5		ENSP00000453384.2
ENSG00000259515	ENST00000560931.1	n.164A>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1336334 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 659942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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.: 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

May 16, 2024

The c.5111T>C (p.L1704P) alteration is located in exon 37 (coding exon 37) of the CDC42BPB gene. This alteration results from a T to C substitution at nucleotide position 5111, causing the leucine (L) at amino acid position 1704 to be replaced by a proline (P). 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	0.089
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.27
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.10	T
Polyphen		0.97	D
Vest4		0.46
MutPred		0.11		Gain of relative solvent accessibility (P = 0.0166);
MVP		0.52
MPC		1.4
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.31
gMVP		0.50

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

Other links and lift over

dbSNP: rs1891500276; hg19: chr14-103400074;