chr9-125220578-C-A

Variant names:

• chr9-125220578-C-A
• rs746870481
• NM_005833.4:c.404C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005833.4(RABEPK):​c.404C>A​(p.Pro135Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RABEPK NM_005833.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43
• Publications: 3 publications found

Genes affected

RABEPK (HGNC:16896): (Rab9 effector protein with kelch motifs) Predicted to be involved in receptor-mediated endocytosis and vesicle docking involved in exocytosis. Predicted to be located in cytoplasmic vesicle; cytosol; and trans-Golgi network membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25741053).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005833.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RABEPK	NM_005833.4	MANE Select	c.404C>A	p.Pro135Gln	missense	Exon 5 of 8	NP_005824.2
	RABEPK	NM_001174152.2		c.404C>A	p.Pro135Gln	missense	Exon 6 of 9	NP_001167623.1	Q7Z6M1-1
	RABEPK	NM_001174153.2		c.251C>A	p.Pro84Gln	missense	Exon 5 of 8	NP_001167624.1	Q7Z6M1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RABEPK	ENST00000373538.8	TSL:1 MANE Select	c.404C>A	p.Pro135Gln	missense	Exon 5 of 8	ENSP00000362639.3	Q7Z6M1-1
	RABEPK	ENST00000394125.8	TSL:1	c.404C>A	p.Pro135Gln	missense	Exon 6 of 9	ENSP00000377683.4	Q7Z6M1-1
	RABEPK	ENST00000259460.12	TSL:1	c.251C>A	p.Pro84Gln	missense	Exon 5 of 8	ENSP00000259460.8	Q7Z6M1-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251264 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.4
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.29
Sift	Benign	0.13	T
Sift4G	Benign	0.28	T
Polyphen		1.0	D
Vest4		0.39
MutPred		0.17		Loss of glycosylation at P135 (P = 0.0057)
MVP		0.76
MPC		0.21
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.16
gMVP		0.58
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs746870481; hg19: chr9-127982857;