rs3791851

Variant names:

• chr2-170842162-T-C
• rs3791851
• NM_000817.3:c.639-1883T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000817.3(GAD1):​c.639-1883T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 152,054 control chromosomes in the GnomAD database, including 4,244 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4244 hom., cov: 32)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.257
• Publications: 5 publications found

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]

GAD1 Gene-Disease associations (from GenCC):

• early infantile epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy 89

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• spastic quadriplegic cerebral palsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• cerebral palsy, spastic quadriplegic, 1

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000817.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	NM_000817.3	MANE Select	c.639-1883T>C		intron	N/A	NP_000808.2	Q99259-1
	GAD1	NM_013445.4		c.639-407T>C		intron	N/A	NP_038473.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000358196.8	TSL:1 MANE Select	c.639-1883T>C		intron	N/A	ENSP00000350928.3	Q99259-1
	GAD1	ENST00000375272.5	TSL:1	c.639-407T>C		intron	N/A	ENSP00000364421.1	Q99259-3
	GAD1	ENST00000493875.5	TSL:1	n.639-1883T>C		intron	N/A	ENSP00000434696.1	Q99259-4

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34194 AN: 151936 Hom.: 4241 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.220

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.225 AC: 34221 AN: 152054 Hom.: 4244 Cov.: 32 AF XY: 0.229 AC XY: 17002 AN XY: 74322

African (AFR) AF: 0.129 AC: 5363 AN: 41496

American (AMR) AF: 0.178 AC: 2722 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 807 AN: 3470

East Asian (EAS) AF: 0.294 AC: 1522 AN: 5170

South Asian (SAS) AF: 0.370 AC: 1783 AN: 4814

European-Finnish (FIN) AF: 0.316 AC: 3347 AN: 10576

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17965 AN: 67948

Other (OTH) AF: 0.224 AC: 472 AN: 2110

Alfa AF: 0.235 Hom.: 578

Bravo AF: 0.209

Asia WGS AF: 0.319 AC: 1106 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.5
DANN	Benign	0.42
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs3791851; hg19: chr2-171698672;