chr22-22646770-C-T

Variant names:

• chr22-22646770-C-T
• rs572265533
• NM_199127.3:c.193C>T

Variant summary

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

The NM_199127.3(GGTLC2):​c.193C>T​(p.Arg65Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,610,370 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000044 (1 hom.)
• Consequence: GGTLC2 NM_199127.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86
• Publications: 1 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=0.043742687).

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.193C>T	p.Arg65Cys	missense	Exon 3 of 6	NP_954578.2	Q14390
	GGTLC2	NM_001282879.2		c.193C>T	p.Arg65Cys	missense	Exon 3 of 5	NP_001269808.1	A0A494C1J8
	GGTLC2	NM_001391910.1		c.193C>T	p.Arg65Cys	missense	Exon 3 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.193C>T	p.Arg65Cys	missense	Exon 3 of 6	ENSP00000415676.2	Q14390
	GGTLC2	ENST00000480559.6	TSL:1	c.193C>T	p.Arg65Cys	missense	Exon 3 of 6	ENSP00000419751.1	Q14390
	GGTLC2	ENST00000417145.2	TSL:2	c.193C>T	p.Arg65Cys	missense	Exon 2 of 4	ENSP00000499086.1	A0A494C1J8

Frequencies

GnomAD3 genomes AF: 0.0000989 AC: 15 AN: 151656 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000835

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000806 AC: 20 AN: 248262 AF XY: 0.000104

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000439 AC: 64 AN: 1458598 Hom.: 1 Cov.: 32 AF XY: 0.0000607 AC XY: 44 AN XY: 725330

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.000112 AC: 5 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25746

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000281 AC: 24 AN: 85378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53162

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5734

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1110504

Other (OTH) AF: 0.0000166 AC: 1 AN: 60272

GnomAD4 genome AF: 0.0000988 AC: 15 AN: 151772 Hom.: 0 Cov.: 28 AF XY: 0.000121 AC XY: 9 AN XY: 74166

African (AFR) AF: 0.000169 AC: 7 AN: 41450

American (AMR) AF: 0.000131 AC: 2 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5016

South Asian (SAS) AF: 0.000836 AC: 4 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67936

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.000115 AC: 14

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	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.78
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.073
Sift	Benign	0.15	T
Sift4G	Benign	0.092	T
Polyphen		0.15	B
Vest4		0.12
MVP		0.22
MPC		0.53
ClinPred		0.041	T
PromoterAI		-0.018	Neutral
Varity_R		0.21
gMVP		0.69
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs572265533; hg19: chr22-22989240;