rs769390

Positions:

• chr2-170836945-A-C
• chr2-170836945-A-G
• chr2-170836945-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000817.3(GAD1):​c.638+62A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,187,206 control chromosomes in the GnomAD database, including 41,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3868 hom., cov: 32)
  • Exomes 𝑓: 0.27 (37655 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.22

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-170836945-A-C is Benign according to our data. Variant chr2-170836945-A-C is described in ClinVar as [Benign]. Clinvar id is 1230108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAD1	NM_000817.3	c.638+62A>C		intron_variant		ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8	c.638+62A>C		intron_variant		1	NM_000817.3	ENSP00000350928.3

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30665 AN: 152064 Hom.: 3865 Cov.: 32

Gnomad AFR AF: 0.0523

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.201

GnomAD4 exome AF: 0.267 AC: 276817 AN: 1035024 Hom.: 37655 AF XY: 0.272 AC XY: 144418 AN XY: 531312

Gnomad4 AFR exome AF: 0.0465

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.217

Gnomad4 EAS exome AF: 0.272

Gnomad4 SAS exome AF: 0.367

Gnomad4 FIN exome AF: 0.313

Gnomad4 NFE exome AF: 0.271

Gnomad4 OTH exome AF: 0.249

GnomAD4 genome AF: 0.202 AC: 30678 AN: 152182 Hom.: 3868 Cov.: 32 AF XY: 0.206 AC XY: 15359 AN XY: 74394

Gnomad4 AFR AF: 0.0522

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.288

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.317

Gnomad4 NFE AF: 0.264

Gnomad4 OTH AF: 0.205

Alfa AF: 0.224 Hom.: 525

Bravo AF: 0.181

Asia WGS AF: 0.309 AC: 1071 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	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.78

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: rs769390; hg19: chr2-171693455;