22-22646472-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_199127.3(GGTLC2):​c.127G>C​(p.Val43Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000386 in 1,553,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. V43I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: GGTLC2 NM_199127.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13817224).

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>C	p.Val43Leu	missense	Exon 2 of 6	NP_954578.2	Q14390
	GGTLC2	NM_001282879.2		c.127G>C	p.Val43Leu	missense	Exon 2 of 5	NP_001269808.1	A0A494C1J8
	GGTLC2	NM_001391910.1		c.127G>C	p.Val43Leu	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>C	p.Val43Leu	missense	Exon 2 of 6	ENSP00000415676.2	Q14390
	GGTLC2	ENST00000480559.6	TSL:1	c.127G>C	p.Val43Leu	missense	Exon 2 of 6	ENSP00000419751.1	Q14390
	GGTLC2	ENST00000417145.2	TSL:2	c.127G>C	p.Val43Leu	missense	Exon 1 of 4	ENSP00000499086.1	A0A494C1J8

Frequencies

GnomAD3 genomes AF: 0.00000678 AC: 1 AN: 147474 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000356 AC: 5 AN: 1406006 Hom.: 0 Cov.: 36 AF XY: 0.00000286 AC XY: 2 AN XY: 698250

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

American (AMR) AF: 0.00 AC: 0 AN: 40030

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 37990

South Asian (SAS) AF: 0.00 AC: 0 AN: 82396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4062

European-Non Finnish (NFE) AF: 0.00000464 AC: 5 AN: 1077054

Other (OTH) AF: 0.00 AC: 0 AN: 58532

GnomAD4 genome AF: 0.00000678 AC: 1 AN: 147474 Hom.: 0 Cov.: 24 AF XY: 0.0000140 AC XY: 1 AN XY: 71608

African (AFR) AF: 0.00 AC: 0 AN: 41012

American (AMR) AF: 0.00 AC: 0 AN: 14684

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4852

South Asian (SAS) AF: 0.00 AC: 0 AN: 4330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66078

Other (OTH) AF: 0.00 AC: 0 AN: 2006

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.3
DANN	Benign	0.68
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.074
Sift	Benign	0.52	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.64		Gain of disorder (P = 0.2306)
MVP		0.014
MPC		0.39
ClinPred		0.17	T
PromoterAI		-0.019	Neutral
Varity_R		0.18
gMVP		0.53
Mutation Taster		=66/34	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: rs556159666; hg19: chr22-22988942;