2-61488644-A-C

Variant names:

• chr2-61488644-A-C
• NM_003400.4:c.2150T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_003400.4(XPO1):​c.2150T>G​(p.Met717Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: XPO1 NM_003400.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.23
• Publications: 0 publications found

Genes affected

XPO1 (HGNC:12825): (exportin 1) This cell-cycle-regulated gene encodes a protein that mediates leucine-rich nuclear export signal (NES)-dependent protein transport. The protein specifically inhibits the nuclear export of Rev and U snRNAs. It is involved in the control of several cellular processes by controlling the localization of cyclin B, MPAK, and MAPKAP kinase 2. This protein also regulates NFAT and AP-1. [provided by RefSeq, Jan 2015]

USP34-DT (HGNC:55262): (USP34 divergent transcript)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 6.0107 (above the threshold of 3.09). Trascript score misZ: 7.9387 (above the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 2-61488644-A-C is Pathogenic according to our data. Variant chr2-61488644-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 4073404.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPO1	NM_003400.4	c.2150T>G	p.Met717Arg	missense_variant	Exon 18 of 25	ENST00000401558.7	NP_003391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPO1	ENST00000401558.7	c.2150T>G	p.Met717Arg	missense_variant	Exon 18 of 25	1	NM_003400.4	ENSP00000384863.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

XPO1-associated Neurodevelopmental Disorder Pathogenic:1

Jul 21, 2025

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG/AMP (Richards et al, 2015): PS2, PM2, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;D;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.8	H;H;H
PhyloP100		9.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.93
MutPred		0.86		Gain of ubiquitination at K722 (P = 0.102);Gain of ubiquitination at K722 (P = 0.102);Gain of ubiquitination at K722 (P = 0.102);
MVP		0.85
MPC		3.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		1.0
Mutation Taster		=18/82	disease causing

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

hg19: chr2-61715779;