Genetic Variant GGTLC2:p.Met130Lys (chr22-22647169-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_199127.3(GGTLC2):c.389T>A(p.Met130Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M130T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GGTLC2
NM_199127.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0610

Publications

0 publications found

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]

GGTLC2 links:

IGL (HGNC:5853):

IGL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199127.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GGTLC2	NM_199127.3	MANE Select	c.389T>A	p.Met130Lys	missense	Exon 5 of 6	NP_954578.2	Q14390
GGTLC2	NM_001282879.2		c.491T>A	p.Met164Lys	missense	Exon 4 of 5	NP_001269808.1	A0A494C1J8
GGTLC2	NM_001391910.1		c.491T>A	p.Met164Lys	missense	Exon 4 of 5	NP_001378839.1	A0A494C1J8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GGTLC2	ENST00000448514.3	TSL:1 MANE Select	c.389T>A	p.Met130Lys	missense	Exon 5 of 6	ENSP00000415676.2	Q14390
GGTLC2	ENST00000480559.6	TSL:1	c.389T>A	p.Met130Lys	missense	Exon 5 of 6	ENSP00000419751.1	Q14390
GGTLC2	ENST00000417145.2	TSL:2	c.491T>A	p.Met164Lys	missense	Exon 3 of 4	ENSP00000499086.1	A0A494C1J8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250476

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.36

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.021

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.28

M_CAP

Benign

0.0015

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.55

PhyloP100

0.061

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.3

REVEL

Benign

0.039

Sift

Benign

0.047

Sift4G

Uncertain

0.026

Polyphen

0.0020

Vest4

0.24

MutPred

0.71

Loss of helix (P = 0.0104)

MVP

0.040

MPC

2.6

ClinPred

0.032

Varity_R

0.33

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.93

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.30

Position offset: -28

DS_AL_spliceai

0.93

Position offset: 8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over