rs769393

Positions:

• chr2-170853011-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000817.3(GAD1):​c.1263+219G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0804 in 608,614 control chromosomes in the GnomAD database, including 3,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (469 hom., cov: 32)
  • Exomes 𝑓: 0.088 (2631 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.36

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-170853011-G-A is Benign according to our data. Variant chr2-170853011-G-A is described in ClinVar as [Benign]. Clinvar id is 1237492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAD1	NM_000817.3	c.1263+219G>A		intron_variant		ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8	c.1263+219G>A		intron_variant		1	NM_000817.3	ENSP00000350928.3

Frequencies

GnomAD3 genomes AF: 0.0586 AC: 8906 AN: 151990 Hom.: 468 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0452

Gnomad ASJ AF: 0.0508

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.0995

Gnomad MID AF: 0.0955

Gnomad NFE AF: 0.0610

Gnomad OTH AF: 0.0504

GnomAD4 exome AF: 0.0877 AC: 40034 AN: 456504 Hom.: 2631 Cov.: 0 AF XY: 0.0944 AC XY: 22881 AN XY: 242366

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.0745

Gnomad4 ASJ exome AF: 0.0517

Gnomad4 EAS exome AF: 0.223

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.0896

Gnomad4 NFE exome AF: 0.0599

Gnomad4 OTH exome AF: 0.0782

GnomAD4 genome AF: 0.0586 AC: 8910 AN: 152110 Hom.: 469 Cov.: 32 AF XY: 0.0634 AC XY: 4715 AN XY: 74330

Gnomad4 AFR AF: 0.0125

Gnomad4 AMR AF: 0.0452

Gnomad4 ASJ AF: 0.0508

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.0995

Gnomad4 NFE AF: 0.0610

Gnomad4 OTH AF: 0.0522

Alfa AF: 0.0547 Hom.: 48

Bravo AF: 0.0523

Asia WGS AF: 0.197 AC: 683 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	20
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs769393; hg19: chr2-171709521;