rs769407

Variant names:

• chr2-170837198-G-C
• rs769407
• NM_000817.3:c.638+315G>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.638+315G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 152,074 control chromosomes in the GnomAD database, including 4,072 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 0.22 (4072 hom., cov: 32)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.852
• Publications: 8 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=-0.63).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.354 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.638+315G>C		intron	N/A	NP_000808.2	Q99259-1
	GAD1	NM_013445.4		c.638+315G>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.638+315G>C		intron	N/A	ENSP00000350928.3	Q99259-1
	GAD1	ENST00000375272.5	TSL:1	c.638+315G>C		intron	N/A	ENSP00000364421.1	Q99259-3
	GAD1	ENST00000493875.5	TSL:1	n.638+315G>C		intron	N/A	ENSP00000434696.1	Q99259-4

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33080 AN: 151958 Hom.: 4069 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.213

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

GnomAD4 genome AF: 0.218 AC: 33106 AN: 152074 Hom.: 4072 Cov.: 32 AF XY: 0.222 AC XY: 16466 AN XY: 74336

African (AFR) AF: 0.108 AC: 4466 AN: 41510

American (AMR) AF: 0.171 AC: 2614 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 780 AN: 3468

East Asian (EAS) AF: 0.287 AC: 1484 AN: 5176

South Asian (SAS) AF: 0.369 AC: 1775 AN: 4814

European-Finnish (FIN) AF: 0.317 AC: 3340 AN: 10550

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17948 AN: 67968

Other (OTH) AF: 0.217 AC: 458 AN: 2112

Alfa AF: 0.234 Hom.: 539

Bravo AF: 0.200

Asia WGS AF: 0.316 AC: 1096 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.84
PhyloP100		0.85
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: rs769407; hg19: chr2-171693708;