NM_004703.6:c.1782C>G

Variant names:

• chr17-5365235-C-G
• rs371641660
• NM_004703.6:c.1782C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004703.6(RABEP1):​c.1782C>G​(p.His594Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RABEP1 NM_004703.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.396
• Publications: 0 publications found

Genes affected

RABEP1 (HGNC:17677): (rabaptin, RAB GTPase binding effector protein 1) Enables protein domain specific binding activity and protein homodimerization activity. Involved in vesicle-mediated transport. Located in endocytic vesicle and endosome. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

NUP88 (HGNC:8067): (nucleoporin 88) The nuclear pore complex is a massive structure that extends across the nuclear envelope, forming a gateway that regulates the flow of macromolecules between the nucleus and the cytoplasm. Nucleoporins, a family of 50 to 100 proteins, are the main components of the nuclear pore complex in eukaryotic cells. The protein encoded by this gene belongs to the nucleoporin family and is associated with the oncogenic nucleoporin CAN/Nup214 in a dynamic subcomplex. This protein is also overexpressed in a large number of malignant neoplasms and precancerous dysplasias. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

NUP88 Gene-Disease associations (from GenCC):

• fetal akinesia deformation sequence 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000263220 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066274345).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004703.6. 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
	RABEP1	NM_004703.6	MANE Select	c.1782C>G	p.His594Gln	missense	Exon 11 of 18	NP_004694.2
	RABEP1	NM_001083585.3		c.1782C>G	p.His594Gln	missense	Exon 11 of 17	NP_001077054.1	Q15276-2
	RABEP1	NM_001291581.2		c.1653C>G	p.His551Gln	missense	Exon 10 of 17	NP_001278510.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RABEP1	ENST00000537505.6	TSL:1 MANE Select	c.1782C>G	p.His594Gln	missense	Exon 11 of 18	ENSP00000445408.2	Q15276-1
	RABEP1	ENST00000341923.10	TSL:1	c.1782C>G	p.His594Gln	missense	Exon 11 of 17	ENSP00000339569.6	Q15276-2
	RABEP1	ENST00000575475.2	TSL:1	n.1818C>G		non_coding_transcript_exon	Exon 10 of 14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450142 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 721978

African (AFR) AF: 0.00 AC: 0 AN: 32844

American (AMR) AF: 0.00 AC: 0 AN: 42354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39384

South Asian (SAS) AF: 0.00 AC: 0 AN: 84756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106068

Other (OTH) AF: 0.00 AC: 0 AN: 59930

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.048
DANN	Benign	0.74
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.40
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.021
Sift	Benign	0.61	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.35		Loss of catalytic residue at H594 (P = 0.1599)
MVP		0.27
ClinPred		0.036	T
GERP RS		-8.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.054
Mutation Taster		=81/19	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: rs371641660; hg19: chr17-5268530;