10-26219100-T-G

Variant names:

• chr10-26219100-T-G
• NM_001134366.2:c.344T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001134366.2(GAD2):​c.344T>G​(p.Met115Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAD2 NM_001134366.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

Genes affected

GAD2 (HGNC:4093): (glutamate decarboxylase 2) This gene encodes one of several forms of glutamic acid decarboxylase, identified as a major autoantigen in insulin-dependent diabetes. The enzyme encoded is responsible for catalyzing the production of gamma-aminobutyric acid from L-glutamic acid. A pathogenic role for this enzyme has been identified in the human pancreas since it has been identified as an autoantibody and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Oct 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.344T>G	p.Met115Arg	missense_variant	Exon 4 of 16	ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.344T>G	p.Met115Arg	missense_variant	Exon 4 of 17		NP_000809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD2	ENST00000376261.8	c.344T>G	p.Met115Arg	missense_variant	Exon 4 of 16	1	NM_001134366.2	ENSP00000365437.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.344T>G (p.M115R) alteration is located in exon 4 (coding exon 4) of the GAD2 gene. This alteration results from a T to G substitution at nucleotide position 344, causing the methionine (M) at amino acid position 115 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	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D;D;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.6	L;L;.
PhyloP100		7.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.5	D;D;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.028	D;D;.
Sift4G	Uncertain	0.048	D;D;.
Polyphen		0.092	B;B;.
Vest4		0.65
MutPred		0.75		Gain of MoRF binding (P = 0.0699);Gain of MoRF binding (P = 0.0699);.;
MVP		0.78
MPC		0.62
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.89
Mutation Taster		=8/192	disease causing

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

hg19: chr10-26508029;