22-22646407-C-G

Variant names:

• chr22-22646407-C-G
• NM_199127.3:c.62C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_199127.3(GGTLC2):​c.62C>G​(p.Pro21Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 17)
• Consequence: GGTLC2 NM_199127.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17643788).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGTLC2	NM_199127.3	c.62C>G	p.Pro21Arg	missense_variant	Exon 2 of 6	ENST00000448514.3	NP_954578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGTLC2	ENST00000448514.3	c.62C>G	p.Pro21Arg	missense_variant	Exon 2 of 6	1	NM_199127.3	ENSP00000415676.2

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.62C>G (p.P21R) alteration is located in exon 1 (coding exon 1) of the GGTLC2 gene. This alteration results from a C to G substitution at nucleotide position 62, causing the proline (P) at amino acid position 21 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	.;.;T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.026	N
LIST_S2	Uncertain	0.94	.;D;D;.
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	.;.;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.4	.;.;D;D
REVEL	Benign	0.11
Sift	Benign	0.077	.;.;T;T
Sift4G	Benign	0.37	T;T;T;T
Polyphen		0.60	.;.;P;.
Vest4		0.31
MutPred		0.54		Loss of glycosylation at T18 (P = 0.0364);Loss of glycosylation at T18 (P = 0.0364);Loss of glycosylation at T18 (P = 0.0364);Loss of glycosylation at T18 (P = 0.0364);
MVP		0.29
MPC		0.88
ClinPred		0.96	D
Varity_R		0.35
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-22988877;