Genetic Variant GGTLC2:p.Thr31Met (chr22-22646437-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02

Publications

1 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017638713).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

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.92C>T	p.Thr31Met	missense	Exon 2 of 6	NP_954578.2	Q14390
GGTLC2	NM_001282879.2		c.92C>T	p.Thr31Met	missense	Exon 2 of 5	NP_001269808.1	A0A494C1J8
GGTLC2	NM_001391910.1		c.92C>T	p.Thr31Met	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.92C>T	p.Thr31Met	missense	Exon 2 of 6	ENSP00000415676.2	Q14390
GGTLC2	ENST00000480559.6	TSL:1	c.92C>T	p.Thr31Met	missense	Exon 2 of 6	ENSP00000419751.1	Q14390
GGTLC2	ENST00000417145.2	TSL:2	c.92C>T	p.Thr31Met	missense	Exon 1 of 4	ENSP00000499086.1	A0A494C1J8

Frequencies

GnomAD3 genomes

AF:

0.000215

AC:

AN:

144494

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000837

AC:

AN:

203174

AF XY:

0.0000183

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000227

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000370

AC:

AN:

1378194

Hom.:

Cov.:

AF XY:

0.0000204

AC XY:

AN XY:

684736

show subpopulations

African (AFR)

AF:

0.000331

AC:

AN:

33186

American (AMR)

AF:

0.000101

AC:

AN:

39524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

37810

South Asian (SAS)

AF:

0.00

AC:

AN:

80380

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3986

European-Non Finnish (NFE)

AF:

0.0000323

AC:

AN:

1052380

Other (OTH)

AF:

0.0000347

AC:

AN:

57620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000214

AC:

AN:

144586

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

69938

show subpopulations

African (AFR)

AF:

0.000686

AC:

AN:

40802

American (AMR)

AF:

0.000141

AC:

AN:

14138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3362

East Asian (EAS)

AF:

0.00

AC:

AN:

4662

South Asian (SAS)

AF:

0.00

AC:

AN:

4072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9668

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.0000154

AC:

AN:

64802

Other (OTH)

AF:

0.00

AC:

AN:

1942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.534

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000142

Hom.:

Bravo

AF:

0.000246

ESP6500AA

AF:

0.00161

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

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

Benign

0.092

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.3

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.0031

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.39

M_CAP

Benign

0.0014

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

1.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.49

REVEL

Benign

0.028

Sift

Benign

0.12

Sift4G

Benign

0.13

Polyphen

0.074

Vest4

0.081

MVP

0.15

MPC

0.40

ClinPred

0.018

PromoterAI

0.0058

Neutral

(source)

Varity_R

0.036

gMVP

0.59

Mutation Taster

=97/3

polymorphism

(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

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over