22-22646472-G-A

Variant names:

• chr22-22646472-G-A
• rs556159666
• NM_199127.3:c.127G>A

Variant summary

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

The NM_199127.3(GGTLC2):​c.127G>A​(p.Val43Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,553,556 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00020 (7 hom.)
• Consequence: GGTLC2 NM_199127.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03918892).
• BS2: High Homozygotes in GnomAdExome4 at 7 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.127G>A	p.Val43Ile	missense	Exon 2 of 6	NP_954578.2	Q14390
	GGTLC2	NM_001282879.2		c.127G>A	p.Val43Ile	missense	Exon 2 of 5	NP_001269808.1	A0A494C1J8
	GGTLC2	NM_001391910.1		c.127G>A	p.Val43Ile	missense	Exon 2 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.127G>A	p.Val43Ile	missense	Exon 2 of 6	ENSP00000415676.2	Q14390
	GGTLC2	ENST00000480559.6	TSL:1	c.127G>A	p.Val43Ile	missense	Exon 2 of 6	ENSP00000419751.1	Q14390
	GGTLC2	ENST00000417145.2	TSL:2	c.127G>A	p.Val43Ile	missense	Exon 1 of 4	ENSP00000499086.1	A0A494C1J8

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 28 AN: 147472 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000824

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000303

Gnomad OTH AF: 0.000499

GnomAD2 exomes AF: 0.000173 AC: 35 AN: 202354 AF XY: 0.000201

Gnomad AFR exome AF: 0.0000697

Gnomad AMR exome AF: 0.000210

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000404

Gnomad FIN exome AF: 0.000128

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000380

GnomAD4 exome AF: 0.000196 AC: 276 AN: 1405990 Hom.: 7 Cov.: 36 AF XY: 0.000205 AC XY: 143 AN XY: 698242

African (AFR) AF: 0.00 AC: 0 AN: 33180

American (AMR) AF: 0.000200 AC: 8 AN: 40030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25564

East Asian (EAS) AF: 0.00205 AC: 78 AN: 37990

South Asian (SAS) AF: 0.0000243 AC: 2 AN: 82396

European-Finnish (FIN) AF: 0.000403 AC: 19 AN: 47198

Middle Eastern (MID) AF: 0.000246 AC: 1 AN: 4062

European-Non Finnish (NFE) AF: 0.000149 AC: 160 AN: 1077038

Other (OTH) AF: 0.000137 AC: 8 AN: 58532

GnomAD4 genome AF: 0.000190 AC: 28 AN: 147566 Hom.: 0 Cov.: 24 AF XY: 0.000112 AC XY: 8 AN XY: 71724

African (AFR) AF: 0.0000486 AC: 2 AN: 41126

American (AMR) AF: 0.00 AC: 0 AN: 14704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.000827 AC: 4 AN: 4836

South Asian (SAS) AF: 0.00 AC: 0 AN: 4324

European-Finnish (FIN) AF: 0.000101 AC: 1 AN: 9936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000303 AC: 20 AN: 66068

Other (OTH) AF: 0.000496 AC: 1 AN: 2018

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.000194 AC: 23

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	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.6
DANN	Benign	0.89
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.080
Sift	Benign	0.22	T
Sift4G	Benign	0.31	T
Polyphen		0.0020	B
Vest4		0.068
MutPred		0.58		Loss of disorder (P = 0.1455)
MVP		0.040
MPC		0.32
ClinPred		0.020	T
PromoterAI		0.013	Neutral
Varity_R		0.12
gMVP		0.30
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs556159666; hg19: chr22-22988942; COSMIC: COSV101312273; COSMIC: COSV101312273;