1-89109713-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004120.5(GBP2):​c.1623G>A​(p.Met541Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GBP2
NM_004120.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.551
Variant links:
Genes affected
GBP2 (HGNC:4183): (guanylate binding protein 2) This gene belongs to the guanine-binding protein (GBP) family, which includes interferon-induced proteins that can bind to guanine nucleotides (GMP, GDP and GTP). The encoded protein is a GTPase which hydrolyzes GTP, predominantly to GDP. The protein may play a role as a marker of squamous cell carcinomas. [provided by RefSeq, Jul 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.023430198).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GBP2NM_004120.5 linkc.1623G>A p.Met541Ile missense_variant Exon 10 of 11 ENST00000370466.4 NP_004111.2 P32456Q8TCE5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GBP2ENST00000370466.4 linkc.1623G>A p.Met541Ile missense_variant Exon 10 of 11 1 NM_004120.5 ENSP00000359497.3 P32456
GBP2ENST00000464839.5 linkn.1623G>A non_coding_transcript_exon_variant Exon 13 of 15 2 ENSP00000434282.1 P32456
GBP2ENST00000493802.5 linkn.583G>A non_coding_transcript_exon_variant Exon 4 of 5 3

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251352
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135840
show subpopulations
Gnomad AFR exome
AF:
0.000369
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461752
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727172
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152320
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000718
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 16, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1623G>A (p.M541I) alteration is located in exon 10 (coding exon 9) of the GBP2 gene. This alteration results from a G to A substitution at nucleotide position 1623, causing the methionine (M) at amino acid position 541 to be replaced by an isoleucine (I). 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
0.16
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
0.18
DANN
Benign
0.66
DEOGEN2
Benign
0.039
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.021
N
LIST_S2
Benign
0.054
T
M_CAP
Benign
0.0036
T
MetaRNN
Benign
0.023
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.23
N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.50
N
REVEL
Benign
0.12
Sift
Benign
0.35
T
Sift4G
Benign
0.50
T
Polyphen
0.0
B
Vest4
0.059
MutPred
0.48
Loss of MoRF binding (P = 0.1028);
MVP
0.34
MPC
0.11
ClinPred
0.0048
T
GERP RS
-0.21
Varity_R
0.041
gMVP
0.087

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146553595; hg19: chr1-89575396; API