14-102933818-G-A

Variant names:

• chr14-102933818-G-A
• NM_006035.4:c.5030C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

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
• Publications: 0 publications found

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:58618):

AMN (HGNC:14604): (amnion associated transmembrane protein) The protein encoded by this gene is a type I transmembrane protein. It is thought to modulate bone morphogenetic protein (BMP) receptor function by serving as an accessory or coreceptor, and thus facilitates or hinders BMP binding. It is known that the mouse AMN gene is expressed in the extraembryonic visceral endoderm layer during gastrulation, but it is found to be mutated in amnionless mouse. The encoded protein has sequence similarity to short gastrulation (Sog) and procollagen IIA proteins in Drosophila. [provided by RefSeq, Jul 2008]

AMN Gene-Disease associations (from GenCC):

• Imerslund-Grasbeck syndrome type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Imerslund-Grasbeck syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC42BPB	ENST00000361246.7	c.5030C>T	p.Ser1677Leu	missense_variant	Exon 37 of 37	1	NM_006035.4	ENSP00000355237.2
CDC42BPB	ENST00000559043.2	c.4952C>T	p.Ser1651Leu	missense_variant	Exon 36 of 36	5		ENSP00000453384.2
ENSG00000259515	ENST00000560931.1	n.245G>A		non_coding_transcript_exon_variant	Exon 1 of 2	3
AMN	ENST00000558590.1	n.*222G>A		downstream_gene_variant		2

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

Jul 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		9.5
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
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

hg19: chr14-103400155;