rs928197

Positions:

• chr10-26300696-T-A

Variant summary

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

The NM_001134366.2(GAD2):​c.1585-92T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,204,716 control chromosomes in the GnomAD database, including 25,604 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 (4193 hom., cov: 32)
  • Exomes 𝑓: 0.20 (21411 hom.)
• Consequence: GAD2 NM_001134366.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.908

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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.1585-92T>A		intron_variant		ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.1585-92T>A		intron_variant			NP_000809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAD2	ENST00000376261.8	c.1585-92T>A		intron_variant		1	NM_001134366.2	ENSP00000365437	P1
GAD2	ENST00000259271.7	c.1585-92T>A		intron_variant		1		ENSP00000259271	P1
GAD2	ENST00000648567.1	c.1243-92T>A		intron_variant				ENSP00000498009

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34154 AN: 152004 Hom.: 4191 Cov.: 32

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.229

GnomAD4 exome AF: 0.197 AC: 207684 AN: 1052594 Hom.: 21411 AF XY: 0.198 AC XY: 105535 AN XY: 532596

Gnomad4 AFR exome AF: 0.325

Gnomad4 AMR exome AF: 0.185

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.319

Gnomad4 SAS exome AF: 0.242

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.187

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.225 AC: 34172 AN: 152122 Hom.: 4193 Cov.: 32 AF XY: 0.225 AC XY: 16734 AN XY: 74376

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.305

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.229

Alfa AF: 0.198 Hom.: 382

Bravo AF: 0.232

Asia WGS AF: 0.260 AC: 906 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.7
DANN	Benign	0.83

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: rs928197; hg19: chr10-26589625; COSMIC: COSV52150878;