rs17857149

Positions:

• chr2-170846013-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000817.3(GAD1):​c.952A>G​(p.Lys318Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,504 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAD1 NM_000817.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.97

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GAD1. . Gene score misZ 2.3151 (greater than the threshold 3.09). Trascript score misZ 3.7409 (greater than threshold 3.09). GenCC has associacion of gene with cerebral palsy, spastic quadriplegic, 1, developmental and epileptic encephalopathy 89, early infantile epileptic encephalopathy, spastic quadriplegic cerebral palsy, neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAD1	NM_000817.3	c.952A>G	p.Lys318Glu	missense_variant	10/17	ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8	c.952A>G	p.Lys318Glu	missense_variant	10/17	1	NM_000817.3	ENSP00000350928.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460504 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	.;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.046	D;D
Polyphen		0.79	.;P
Vest4		0.37
MutPred		0.71		Loss of ubiquitination at K318 (P = 0.0283);Loss of ubiquitination at K318 (P = 0.0283);
MVP		0.66
MPC		1.0
ClinPred		0.95	D
GERP RS		5.9
Varity_R		0.93
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs17857149; hg19: chr2-171702523;