rs2839671

Positions:

• chr10-26216893-G-A
• chr10-26216893-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134366.2(GAD2):​c.76+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,604,314 control chromosomes in the GnomAD database, including 29,961 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (3487 hom., cov: 33)
  • Exomes 𝑓: 0.19 (26474 hom.)
• Consequence: GAD2 NM_001134366.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001119
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25

Genes affected

GAD2 (HGNC:4093): (glutamate decarboxylase 2) 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 autoantibody and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD2	NM_001134366.2	c.76+8G>A		splice_region_variant, intron_variant		ENST00000376261.8
GAD2	NM_000818.3	c.76+8G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD2	ENST00000376261.8	c.76+8G>A		splice_region_variant, intron_variant		1	NM_001134366.2	P1
GAD2	ENST00000259271.7	c.76+8G>A		splice_region_variant, intron_variant		1		P1
GAD2	ENST00000428517.2	c.76+8G>A		splice_region_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31352 AN: 152096 Hom.: 3483 Cov.: 33

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.224

GnomAD3 exomes AF: 0.197 AC: 47280 AN: 240218 Hom.: 4927 AF XY: 0.197 AC XY: 25674 AN XY: 130528

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.297

Gnomad SAS exome AF: 0.227

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.186 AC: 270054 AN: 1452100 Hom.: 26474 Cov.: 30 AF XY: 0.187 AC XY: 135236 AN XY: 722154

Gnomad4 AFR exome AF: 0.269

Gnomad4 AMR exome AF: 0.204

Gnomad4 ASJ exome AF: 0.161

Gnomad4 EAS exome AF: 0.360

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.191

GnomAD4 genome AF: 0.206 AC: 31378 AN: 152214 Hom.: 3487 Cov.: 33 AF XY: 0.208 AC XY: 15446 AN XY: 74422

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.210

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.318

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.225

Alfa AF: 0.183 Hom.: 669

Bravo AF: 0.215

Asia WGS AF: 0.272 AC: 947 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.9
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0
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: rs2839671; hg19: chr10-26505822; COSMIC: COSV52150860; COSMIC: COSV52150860;