rs17857148

Positions:

• chr2-170845710-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The ENST00000358196.8(GAD1):​c.872A>G​(p.His291Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GAD1 ENST00000358196.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.95

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 Likely_pathogenic. Variant got 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAD1	NM_000817.3	c.872A>G	p.His291Arg	missense_variant	9/17	ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8	c.872A>G	p.His291Arg	missense_variant	9/17	1	NM_000817.3	ENSP00000350928	P1
GAD1	ENST00000493875.5	c.872A>G	p.His291Arg	missense_variant, NMD_transcript_variant	8/17	1		ENSP00000434696
GAD1	ENST00000625689.2	c.872A>G	p.His291Arg	missense_variant	9/18	5		ENSP00000486612
GAD1	ENST00000414527.6	c.*57A>G		3_prime_UTR_variant, NMD_transcript_variant	8/16	5		ENSP00000403849

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	4.2	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.1	.;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.96
MutPred		0.92		Gain of catalytic residue at H291 (P = 0.0117);Gain of catalytic residue at H291 (P = 0.0117);
MVP		0.93
MPC		1.7
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		1.0

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: rs17857148; hg19: chr2-171702220;