Genetic Variant GGTLC2:p.Thr53Ile (chr22-22646503-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_199127.3(GGTLC2):c.158C>T(p.Thr53Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000671 in 148,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GGTLC2
NM_199127.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.08

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.76

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.158C>T	p.Thr53Ile	missense	Exon 2 of 6	NP_954578.2	Q14390
GGTLC2	NM_001282879.2		c.158C>T	p.Thr53Ile	missense	Exon 2 of 5	NP_001269808.1	A0A494C1J8
GGTLC2	NM_001391910.1		c.158C>T	p.Thr53Ile	missense	Exon 2 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.158C>T	p.Thr53Ile	missense	Exon 2 of 6	ENSP00000415676.2	Q14390
GGTLC2	ENST00000480559.6	TSL:1	c.158C>T	p.Thr53Ile	missense	Exon 2 of 6	ENSP00000419751.1	Q14390
GGTLC2	ENST00000417145.2	TSL:2	c.158C>T	p.Thr53Ile	missense	Exon 1 of 4	ENSP00000499086.1	A0A494C1J8

Frequencies

GnomAD3 genomes

AF:

0.00000671

AC:

AN:

148954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000211

AC:

AN:

1420982

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

704784

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32848

American (AMR)

AF:

0.0000254

AC:

AN:

39296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25634

East Asian (EAS)

AF:

0.00

AC:

AN:

37536

South Asian (SAS)

AF:

0.00

AC:

AN:

82646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4098

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1092926

Other (OTH)

AF:

0.00

AC:

AN:

58990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000671

AC:

AN:

148954

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72422

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41090

American (AMR)

AF:

0.00

AC:

AN:

14852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3426

East Asian (EAS)

AF:

0.00

AC:

AN:

4914

South Asian (SAS)

AF:

0.00

AC:

AN:

4454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66842

Other (OTH)

AF:

0.00

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.091

Eigen

Benign

-0.010

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.73

LIST_S2

Pathogenic

1.0

M_CAP

Benign

0.0040

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.6

PhyloP100

5.1

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.5

REVEL

Benign

0.25

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.68

MVP

0.19

MPC

1.2

ClinPred

0.99

PromoterAI

0.036

Neutral

(source)

Varity_R

0.78

gMVP

0.93

Mutation Taster

=21/79

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over