chr22-22646437-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_199127.3(GGTLC2):​c.92C>T​(p.Thr31Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000538 in 1,522,780 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 1 hom., cov: 21)
Exomes 𝑓: 0.000037 ( 3 hom. )

Consequence

GGTLC2
NM_199127.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.017638713).
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GGTLC2NM_199127.3 linkc.92C>T p.Thr31Met missense_variant Exon 2 of 6 ENST00000448514.3 NP_954578.2 Q14390

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GGTLC2ENST00000448514.3 linkc.92C>T p.Thr31Met missense_variant Exon 2 of 6 1 NM_199127.3 ENSP00000415676.2 Q14390

Frequencies

GnomAD3 genomes
AF:
0.000215
AC:
31
AN:
144494
Hom.:
1
Cov.:
21
show subpopulations
Gnomad AFR
AF:
0.000688
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000142
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:
0.0000154
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000837
AC:
17
AN:
203174
Hom.:
3
AF XY:
0.0000183
AC XY:
2
AN XY:
109324
show subpopulations
Gnomad AFR exome
AF:
0.000587
Gnomad AMR exome
AF:
0.000210
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:
0.0000227
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000370
AC:
51
AN:
1378194
Hom.:
3
Cov.:
35
AF XY:
0.0000204
AC XY:
14
AN XY:
684736
show subpopulations
Gnomad4 AFR exome
AF:
0.000331
Gnomad4 AMR exome
AF:
0.000101
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:
0.0000323
Gnomad4 OTH exome
AF:
0.0000347
GnomAD4 genome
AF:
0.000214
AC:
31
AN:
144586
Hom.:
1
Cov.:
21
AF XY:
0.000229
AC XY:
16
AN XY:
69938
show subpopulations
Gnomad4 AFR
AF:
0.000686
Gnomad4 AMR
AF:
0.000141
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000154
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.000246
ESP6500AA
AF:
0.00161
AC:
7
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000107
AC:
12

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 04, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.92C>T (p.T31M) alteration is located in exon 1 (coding exon 1) of the GGTLC2 gene. This alteration results from a C to T substitution at nucleotide position 92, causing the threonine (T) at amino acid position 31 to be replaced by a methionine (M). 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
0.092
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
7.3
DANN
Benign
0.91
DEOGEN2
Benign
0.0031
.;.;T;.
Eigen
Benign
-0.93
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.010
N
LIST_S2
Benign
0.39
.;T;T;.
M_CAP
Benign
0.0014
T
MetaRNN
Benign
0.018
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
.;.;L;.
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-0.49
.;.;N;N
REVEL
Benign
0.028
Sift
Benign
0.12
.;.;T;T
Sift4G
Benign
0.13
T;T;T;T
Polyphen
0.074
.;.;B;.
Vest4
0.081
MVP
0.15
MPC
0.40
ClinPred
0.018
T
Varity_R
0.036
gMVP
0.59

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: rs147760451; hg19: chr22-22988907; API