16-28906121-G-A

Variant names:

• chr16-28906121-G-A
• rs750752217
• NM_024816.3:c.1321C>T

Variant summary

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

The NM_024816.3(RABEP2):​c.1321C>T​(p.Arg441Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000773 in 1,577,376 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R441H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: RABEP2 NM_024816.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14
• Publications: 0 publications found

Genes affected

RABEP2 (HGNC:24817): (rabaptin, RAB GTPase binding effector protein 2) Predicted to enable GTPase activator activity and growth factor activity. Involved in regulation of cilium assembly. Located in cytosol; intracellular membrane-bounded organelle; and microtubule organizing center. [provided by Alliance of Genome Resources, Apr 2022]

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
RABEP2	NM_024816.3	c.1321C>T	p.Arg441Cys	missense_variant	Exon 9 of 13	ENST00000358201.9	NP_079092.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RABEP2	ENST00000358201.9	c.1321C>T	p.Arg441Cys	missense_variant	Exon 9 of 13	1	NM_024816.3	ENSP00000350934.4
RABEP2	ENST00000357573.10	c.1225C>T	p.Arg409Cys	missense_variant	Exon 8 of 11	1		ENSP00000350186.6
RABEP2	ENST00000544477.5	c.1108C>T	p.Arg370Cys	missense_variant	Exon 8 of 12	2		ENSP00000442798.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000971 AC: 17 AN: 175100 AF XY: 0.000104

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.000151

Gnomad ASJ exome AF: 0.000693

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000823

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000772 AC: 110 AN: 1425194 Hom.: 0 Cov.: 34 AF XY: 0.0000736 AC XY: 52 AN XY: 706380

African (AFR) AF: 0.0000308 AC: 1 AN: 32520

American (AMR) AF: 0.000132 AC: 5 AN: 37980

Ashkenazi Jewish (ASJ) AF: 0.000510 AC: 13 AN: 25494

East Asian (EAS) AF: 0.00 AC: 0 AN: 37418

South Asian (SAS) AF: 0.00 AC: 0 AN: 82280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47918

Middle Eastern (MID) AF: 0.000186 AC: 1 AN: 5370

European-Non Finnish (NFE) AF: 0.0000747 AC: 82 AN: 1097120

Other (OTH) AF: 0.000135 AC: 8 AN: 59094

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74346

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000597 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1321C>T (p.R441C) alteration is located in exon 9 (coding exon 9) of the RABEP2 gene. This alteration results from a C to T substitution at nucleotide position 1321, causing the arginine (R) at amino acid position 441 to be replaced by a cysteine (C). 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	0.33
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.4	.;M;.
PhyloP100		3.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.70
MutPred		0.56		.;Loss of MoRF binding (P = 0.0099);.;
MVP		0.68
MPC		0.71
ClinPred		0.46	T
GERP RS		3.5
Varity_R		0.39
gMVP		0.49
Mutation Taster		=67/33	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: rs750752217; hg19: chr16-28917442;