22-22647013-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_199127.3(GGTLC2):​c.335C>T​(p.Thr112Met) variant causes a missense change. The variant allele was found at a frequency of 0.00667 in 1,611,660 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts 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. T112K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0064 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0067 (52 hom.)
• Consequence: GGTLC2 NM_199127.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008068025).
• BS2: High Homozygotes in GnomAd4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGTLC2	NM_199127.3	MANE Select	c.335C>T	p.Thr112Met	missense	Exon 4 of 6	NP_954578.2	Q14390
	GGTLC2	NM_001282879.2		c.335C>T	p.Thr112Met	missense	Exon 4 of 5	NP_001269808.1	A0A494C1J8
	GGTLC2	NM_001391910.1		c.335C>T	p.Thr112Met	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>T	p.Thr112Met	missense	Exon 4 of 6	ENSP00000415676.2	Q14390
	GGTLC2	ENST00000480559.6	TSL:1	c.335C>T	p.Thr112Met	missense	Exon 4 of 6	ENSP00000419751.1	Q14390
	GGTLC2	ENST00000417145.2	TSL:2	c.335C>T	p.Thr112Met	missense	Exon 3 of 4	ENSP00000499086.1	A0A494C1J8

Frequencies

GnomAD3 genomes AF: 0.00637 AC: 968 AN: 151928 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.0659

Gnomad AMR AF: 0.00322

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00578 AC: 1449 AN: 250832 AF XY: 0.00580

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.00815

Gnomad OTH exome AF: 0.00556

GnomAD4 exome AF: 0.00670 AC: 9778 AN: 1459618 Hom.: 52 Cov.: 36 AF XY: 0.00664 AC XY: 4819 AN XY: 726128

African (AFR) AF: 0.000808 AC: 27 AN: 33404

American (AMR) AF: 0.00246 AC: 110 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000975 AC: 84 AN: 86164

European-Finnish (FIN) AF: 0.0161 AC: 857 AN: 53356

Middle Eastern (MID) AF: 0.000481 AC: 2 AN: 4154

European-Non Finnish (NFE) AF: 0.00755 AC: 8391 AN: 1111796

Other (OTH) AF: 0.00475 AC: 286 AN: 60204

GnomAD4 genome AF: 0.00637 AC: 969 AN: 152042 Hom.: 4 Cov.: 31 AF XY: 0.00680 AC XY: 505 AN XY: 74288

African (AFR) AF: 0.00154 AC: 64 AN: 41502

American (AMR) AF: 0.00321 AC: 49 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5056

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10616

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.00816 AC: 555 AN: 68004

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00352 Hom.: 1

Bravo AF: 0.00519

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00609 AC: 739

EpiCase AF: 0.00573

EpiControl AF: 0.00522

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.15
Sift	Benign	0.048	D
Sift4G	Uncertain	0.051	T
Polyphen		0.43	B
Vest4		0.44
MVP		0.092
MPC		0.47
ClinPred		0.030	T
Varity_R		0.074
gMVP		0.70
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV101312277; COSMIC: COSV101312277;