22-22647013-C-A

Variant names:

• chr22-22647013-C-A
• rs150559361
• NM_199127.3:c.335C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_199127.3(GGTLC2):​c.335C>A​(p.Thr112Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,932 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: GGTLC2 NM_199127.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08
• Publications: 5 publications found

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]

IGL (HGNC:5853):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGTLC2	NM_199127.3	MANE Select	c.335C>A	p.Thr112Lys	missense	Exon 4 of 6	NP_954578.2	Q14390
	GGTLC2	NM_001282879.2		c.335C>A	p.Thr112Lys	missense	Exon 4 of 5	NP_001269808.1	A0A494C1J8
	GGTLC2	NM_001391910.1		c.335C>A	p.Thr112Lys	missense	Exon 4 of 5	NP_001378839.1	A0A494C1J8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGTLC2	ENST00000448514.3	TSL:1 MANE Select	c.335C>A	p.Thr112Lys	missense	Exon 4 of 6	ENSP00000415676.2	Q14390
	GGTLC2	ENST00000480559.6	TSL:1	c.335C>A	p.Thr112Lys	missense	Exon 4 of 6	ENSP00000419751.1	Q14390
	GGTLC2	ENST00000417145.2	TSL:2	c.335C>A	p.Thr112Lys	missense	Exon 3 of 4	ENSP00000499086.1	A0A494C1J8

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151932 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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 Cov.: 36

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151932 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74164

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.0000656 AC: 1 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5068

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0021	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		5.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Polyphen		0.87	P
Vest4		0.52
MutPred		0.73		Gain of methylation at T112 (P = 0.0087)
MVP		0.13
MPC		0.94
ClinPred		0.76	D
Varity_R		0.72
gMVP		0.79
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs150559361; hg19: chr22-22989483;