rs2839677

chr10-26246008-C-T

Variant summary

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

The NM_001134366.2(GAD2):c.920+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0813 in 1,611,080 control chromosomes in the GnomAD database, including 5,916 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 0.065 (401 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5515 hom.)
• Consequence: GAD2 NM_001134366.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002904
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05

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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD2	NM_001134366.2	c.920+8C>T		splice_region_variant, intron_variant		ENST00000376261.8
GAD2	NM_000818.3	c.920+8C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD2	ENST00000376261.8	c.920+8C>T		splice_region_variant, intron_variant		1	NM_001134366.2	P1
GAD2	ENST00000259271.7	c.920+8C>T		splice_region_variant, intron_variant		1		P1
GAD2	ENST00000648567.1	c.578+8C>T		splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9871 AN: 152102 Hom.: 401 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0760

Gnomad ASJ AF: 0.0999

Gnomad EAS AF: 0.0503

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.0767

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0905

Gnomad OTH AF: 0.0718

GnomAD3 exomes AF: 0.0688 AC: 17190 AN: 250012 Hom.: 703 AF XY: 0.0692 AC XY: 9349 AN XY: 135174

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.0487

Gnomad ASJ exome AF: 0.0940

Gnomad EAS exome AF: 0.0561

Gnomad SAS exome AF: 0.0245

Gnomad FIN exome AF: 0.0776

Gnomad NFE exome AF: 0.0918

Gnomad OTH exome AF: 0.0755

GnomAD4 exome AF: 0.0830 AC: 121099 AN: 1458860 Hom.: 5515 Cov.: 30 AF XY: 0.0817 AC XY: 59308 AN XY: 725838

Gnomad4 AFR exome AF: 0.0154

Gnomad4 AMR exome AF: 0.0514

Gnomad4 ASJ exome AF: 0.0932

Gnomad4 EAS exome AF: 0.0462

Gnomad4 SAS exome AF: 0.0257

Gnomad4 FIN exome AF: 0.0804

Gnomad4 NFE exome AF: 0.0923

Gnomad4 OTH exome AF: 0.0817

GnomAD4 genome AF: 0.0648 AC: 9863 AN: 152220 Hom.: 401 Cov.: 32 AF XY: 0.0642 AC XY: 4781 AN XY: 74420

Gnomad4 AFR AF: 0.0185

Gnomad4 AMR AF: 0.0759

Gnomad4 ASJ AF: 0.0999

Gnomad4 EAS AF: 0.0501

Gnomad4 SAS AF: 0.0249

Gnomad4 FIN AF: 0.0767

Gnomad4 NFE AF: 0.0904

Gnomad4 OTH AF: 0.0710

Alfa AF: 0.0808 Hom.: 241

Bravo AF: 0.0652

Asia WGS AF: 0.0440 AC: 155 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.11
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0020
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: rs2839677; hg19: chr10-26534937;