2-170822115-T-G

Position:

• chr2-170822115-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000817.3(GAD1):​c.111T>G​(p.His37Gln) 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H37H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GAD1 NM_000817.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.140

Genes affected

GAD1 (HGNC:4092): (glutamate decarboxylase 1) 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 autoantigen and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Deficiency in this enzyme has been shown to lead to pyridoxine dependency with seizures. Alternative splicing of this gene results in two products, the predominant 67-kD form and a less-frequent 25-kD form. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GAD1
• BP4: Computational evidence support a benign effect (MetaRNN=0.20686522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD1	NM_000817.3	c.111T>G	p.His37Gln	missense_variant	3/17	ENST00000358196.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD1	ENST00000358196.8	c.111T>G	p.His37Gln	missense_variant	3/17	1	NM_000817.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	15
DANN	Benign	0.77
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.85
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;T;T;T;T;.;D;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D;D;.;N;N;N;D;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D;.;T;T;T;D;T
Sift4G	Uncertain	0.026	D;D;T;T;T;T;D;D
Polyphen		0.0, 0.021	.;.;.;B;B;B;.;.
Vest4		0.59, 0.50, 0.52, 0.51
MutPred		0.43		Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);
MVP		0.75
MPC		1.6
ClinPred		0.76	D
GERP RS		-1.7
Varity_R		0.059
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs769404; hg19: chr2-171678625;