rs146282307

Variant names:

• chr22-22646998-C-G
• rs146282307
• NM_199127.3:c.320C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-22646998-C-G
• chr22-22646998-C-T
• chr22-22646998-C-A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_199127.3(GGTLC2):​c.320C>G​(p.Ser107Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,611,550 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S107L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GGTLC2 NM_199127.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

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.320C>G	p.Ser107Trp	missense	Exon 4 of 6	NP_954578.2	Q14390
	GGTLC2	NM_001282879.2		c.320C>G	p.Ser107Trp	missense	Exon 4 of 5	NP_001269808.1	A0A494C1J8
	GGTLC2	NM_001391910.1		c.320C>G	p.Ser107Trp	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.320C>G	p.Ser107Trp	missense	Exon 4 of 6	ENSP00000415676.2	Q14390
	GGTLC2	ENST00000480559.6	TSL:1	c.320C>G	p.Ser107Trp	missense	Exon 4 of 6	ENSP00000419751.1	Q14390
	GGTLC2	ENST00000417145.2	TSL:2	c.320C>G	p.Ser107Trp	missense	Exon 3 of 4	ENSP00000499086.1	A0A494C1J8

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151914 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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 AF: 6.85e-7 AC: 1 AN: 1459636 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726134

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4178

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111800

Other (OTH) AF: 0.0000166 AC: 1 AN: 60206

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151914 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74160

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.0000657 AC: 1 AN: 15222

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.71
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.056
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.23	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.0098	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	4.6	H
PhyloP100		5.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.87		Loss of disorder (P = 5e-04)
MVP		0.44
MPC		1.4
ClinPred		1.0	D
Varity_R		0.82
gMVP		0.94
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs146282307; hg19: chr22-22989468;