22-22647145-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_199127.3(GGTLC2):​c.365C>A​(p.Pro122Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

GGTLC2
NM_199127.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.944
Variant links:
Genes affected
GGTLC2 (HGNC:18596): (gamma-glutamyltransferase light chain 2) This gene encodes a protein related to enzymes that cleaves gamma-glutamyl peptide bonds in glutathione and other peptides. Unlike similar proteins, the encoded protein contains only the light chain portion and may not have catalytic activity. Alternative splicing results in multiple transcript variants. There are several related family members and related pseudogene for this gene situated in the same region of chromosome 22. [provided by RefSeq, Sep 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12496418).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GGTLC2NM_199127.3 linkc.365C>A p.Pro122Gln missense_variant Exon 5 of 6 ENST00000448514.3 NP_954578.2 Q14390

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GGTLC2ENST00000448514.3 linkc.365C>A p.Pro122Gln missense_variant Exon 5 of 6 1 NM_199127.3 ENSP00000415676.2 Q14390

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151920
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00000399
AC:
1
AN:
250734
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135570
show subpopulations
Gnomad AFR exome
AF:
0.0000619
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
Data not reliable, filtered out with message: AS_VQSR
AF:
6.85e-7
AC:
1
AN:
1459652
Hom.:
0
Cov.:
36
AF XY:
0.00
AC XY:
0
AN XY:
726138
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
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:
0.00000658
AC:
1
AN:
151920
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74158
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 13, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.365C>A (p.P122Q) alteration is located in exon 4 (coding exon 4) of the GGTLC2 gene. This alteration results from a C to A substitution at nucleotide position 365, causing the proline (P) at amino acid position 122 to be replaced by a glutamine (Q). 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
0.095
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
0.46
DANN
Benign
0.73
DEOGEN2
Benign
0.00026
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.0045
N
LIST_S2
Benign
0.38
T
M_CAP
Benign
0.0028
T
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-0.92
T
MutationAssessor
Uncertain
2.5
M
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
1.3
N
REVEL
Benign
0.045
Sift
Benign
0.15
T
Sift4G
Benign
0.60
T
Polyphen
0.050
B
Vest4
0.48
MutPred
0.40
Loss of glycosylation at P122 (P = 0.0316);
MVP
0.14
MPC
2.2
ClinPred
0.037
T
Varity_R
0.092

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs753467544; hg19: chr22-22989615; API