22-22647169-T-C

Variant names:

• chr22-22647169-T-C
• rs375757041
• NM_199127.3:c.389T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_199127.3(GGTLC2):​c.389T>C​(p.Met130Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,611,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: GGTLC2 NM_199127.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0610
• 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_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033609092).

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.389T>C	p.Met130Thr	missense	Exon 5 of 6	NP_954578.2	Q14390
	GGTLC2	NM_001282879.2		c.491T>C	p.Met164Thr	missense	Exon 4 of 5	NP_001269808.1	A0A494C1J8
	GGTLC2	NM_001391910.1		c.491T>C	p.Met164Thr	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.389T>C	p.Met130Thr	missense	Exon 5 of 6	ENSP00000415676.2	Q14390
	GGTLC2	ENST00000480559.6	TSL:1	c.389T>C	p.Met130Thr	missense	Exon 5 of 6	ENSP00000419751.1	Q14390
	GGTLC2	ENST00000417145.2	TSL:2	c.491T>C	p.Met164Thr	missense	Exon 3 of 4	ENSP00000499086.1	A0A494C1J8

Frequencies

GnomAD3 genomes AF: 0.0000791 AC: 12 AN: 151790 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000399 AC: 10 AN: 250476 AF XY: 0.0000443

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000186 AC: 272 AN: 1459570 Hom.: 0 Cov.: 35 AF XY: 0.000172 AC XY: 125 AN XY: 726088

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33404

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000726 AC: 3 AN: 4134

European-Non Finnish (NFE) AF: 0.000229 AC: 255 AN: 1111738

Other (OTH) AF: 0.000199 AC: 12 AN: 60200

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000791 AC: 12 AN: 151790 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74086

African (AFR) AF: 0.0000242 AC: 1 AN: 41348

American (AMR) AF: 0.0000657 AC: 1 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5058

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67972

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

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	Benign	0.15
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.10
DANN	Benign	0.73
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-3.4	N
PhyloP100		0.061
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.051
Sift	Benign	0.67	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.030
MPC		2.1
ClinPred		0.058	T
Varity_R		0.070
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs375757041; hg19: chr22-22989639;