chr16-28905420-C-G

Variant names:

• chr16-28905420-C-G
• rs774012300
• NM_024816.3:c.1585G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024816.3(RABEP2):​c.1585G>C​(p.Val529Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,454,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V529M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RABEP2 NM_024816.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.24
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RABEP2	NM_024816.3	c.1585G>C	p.Val529Leu	missense_variant	Exon 12 of 13	ENST00000358201.9	NP_079092.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RABEP2	ENST00000358201.9	c.1585G>C	p.Val529Leu	missense_variant	Exon 12 of 13	1	NM_024816.3	ENSP00000350934.4
RABEP2	ENST00000357573.10	c.1477G>C	p.Val493Leu	missense_variant	Exon 10 of 11	1		ENSP00000350186.6
RABEP2	ENST00000544477.5	c.1372G>C	p.Val458Leu	missense_variant	Exon 11 of 12	2		ENSP00000442798.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454462 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 722826

African (AFR) AF: 0.0000598 AC: 2 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 43630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25772

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.00 AC: 0 AN: 84356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109690

Other (OTH) AF: 0.00 AC: 0 AN: 60144

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	0.058	D
MutationAssessor	Uncertain	2.6	.;M;.
PhyloP100		5.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D;D;D
Sift4G	Benign	0.31	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.73
MutPred		0.18		.;Loss of MoRF binding (P = 0.0979);.;
MVP		0.80
MPC		0.60
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.32
gMVP		0.38
Mutation Taster		=60/40	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: rs774012300; hg19: chr16-28916741;