10-26246008-C-T

Variant names:

• chr10-26246008-C-T
• rs2839677
• NM_001134366.2:c.920+8C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.920+8C>T		splice_region_variant, intron_variant	Intron 8 of 15	ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.920+8C>T		splice_region_variant, intron_variant	Intron 8 of 16		NP_000809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD2	ENST00000376261.8	c.920+8C>T		splice_region_variant, intron_variant	Intron 8 of 15	1	NM_001134366.2	ENSP00000365437.3
GAD2	ENST00000259271.7	c.920+8C>T		splice_region_variant, intron_variant	Intron 8 of 16	1		ENSP00000259271.3
GAD2	ENST00000648567.1	c.578+8C>T		splice_region_variant, intron_variant	Intron 8 of 16			ENSP00000498009.1

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

GnomAD2 exomes AF: 0.0688 AC: 17190 AN: 250012 AF XY: 0.0692

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 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

African (AFR) AF: 0.0154 AC: 516 AN: 33412

American (AMR) AF: 0.0514 AC: 2297 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0932 AC: 2432 AN: 26094

East Asian (EAS) AF: 0.0462 AC: 1829 AN: 39620

South Asian (SAS) AF: 0.0257 AC: 2210 AN: 86128

European-Finnish (FIN) AF: 0.0804 AC: 4291 AN: 53356

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5762

European-Non Finnish (NFE) AF: 0.0923 AC: 102373 AN: 1109550

Other (OTH) AF: 0.0817 AC: 4925 AN: 60270

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

African (AFR) AF: 0.0185 AC: 767 AN: 41552

American (AMR) AF: 0.0759 AC: 1161 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0999 AC: 347 AN: 3472

East Asian (EAS) AF: 0.0501 AC: 259 AN: 5172

South Asian (SAS) AF: 0.0249 AC: 120 AN: 4820

European-Finnish (FIN) AF: 0.0767 AC: 812 AN: 10584

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0904 AC: 6151 AN: 68010

Other (OTH) AF: 0.0710 AC: 150 AN: 2112

Alfa AF: 0.0813 Hom.: 322

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
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2839677; hg19: chr10-26534937;