rs769391

chr2-170852920-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000817.3(GAD1):c.1263+128A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 767,180 control chromosomes in the GnomAD database, including 33,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (6321 hom., cov: 32)
  • Exomes 𝑓: 0.28 (26721 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.329

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-170852920-A-G is Benign according to our data. Variant chr2-170852920-A-G is described in ClinVar as [Benign]. Clinvar id is 1265514.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD1	NM_000817.3	c.1263+128A>G		intron_variant		ENST00000358196.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD1	ENST00000358196.8	c.1263+128A>G		intron_variant		1	NM_000817.3	P1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43611 AN: 151836 Hom.: 6305 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.272

GnomAD4 exome AF: 0.285 AC: 175222 AN: 615224 Hom.: 26721 Cov.: 7 AF XY: 0.290 AC XY: 95390 AN XY: 329114

Gnomad4 AFR exome AF: 0.266

Gnomad4 AMR exome AF: 0.321

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.297

Gnomad4 SAS exome AF: 0.378

Gnomad4 FIN exome AF: 0.314

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.287 AC: 43681 AN: 151956 Hom.: 6321 Cov.: 32 AF XY: 0.291 AC XY: 21571 AN XY: 74254

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.316

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.275

Alfa AF: 0.280 Hom.: 947

Bravo AF: 0.284

Asia WGS AF: 0.349 AC: 1211 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.4
Dann	Benign	0.68

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: rs769391; hg19: chr2-171709430;