17-5386234-T-C

Position:

• chr17-5386234-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002532.6(NUP88):​c.2198A>G​(p.Asn733Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00779 in 1,613,434 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (64 hom.)
• Consequence: NUP88 NM_002532.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.88

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069188774).
• BP6: Variant 17-5386234-T-C is Benign according to our data. Variant chr17-5386234-T-C is described in ClinVar as [Benign]. Clinvar id is 2647295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUP88	NM_002532.6	c.2198A>G	p.Asn733Ser	missense_variant	17/17	ENST00000573584.6
RABEP1	NM_004703.6	c.*3011T>C		3_prime_UTR_variant	18/18	ENST00000537505.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUP88	ENST00000573584.6	c.2198A>G	p.Asn733Ser	missense_variant	17/17	1	NM_002532.6	P1
RABEP1	ENST00000537505.6	c.*3011T>C		3_prime_UTR_variant	18/18	1	NM_004703.6	P1

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 904 AN: 152196 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00925

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00646 AC: 1620 AN: 250726 Hom.: 10 AF XY: 0.00676 AC XY: 916 AN XY: 135552

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000296

Gnomad FIN exome AF: 0.00800

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00638

GnomAD4 exome AF: 0.00798 AC: 11666 AN: 1461120 Hom.: 64 Cov.: 29 AF XY: 0.00785 AC XY: 5706 AN XY: 726898

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00460

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00897

Gnomad4 NFE exome AF: 0.00939

Gnomad4 OTH exome AF: 0.00689

GnomAD4 genome AF: 0.00594 AC: 904 AN: 152314 Hom.: 5 Cov.: 33 AF XY: 0.00581 AC XY: 433 AN XY: 74482

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00753

Gnomad4 NFE AF: 0.00925

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00815 Hom.: 9

Bravo AF: 0.00597

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00919 AC: 79

ExAC AF: 0.00703 AC: 853

EpiCase AF: 0.00922

EpiControl AF: 0.0105

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NUP88-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

NUP88: BS1, BS2; RABEP1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
Sift4G	Uncertain	0.056	T
Polyphen		0.31	B
Vest4		0.34
MVP		0.52
MPC		0.41
ClinPred		0.027	T
GERP RS		3.9
Varity_R		0.16
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs61753103; hg19: chr17-5289554; COSMIC: COSV104997057; COSMIC: COSV104997057;