10-26223115-A-G

Variant names:

• chr10-26223115-A-G
• rs3781117
• NM_001134366.2:c.521-772A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134366.2(GAD2):​c.521-772A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 152,260 control chromosomes in the GnomAD database, including 1,540 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 0.12 (1540 hom., cov: 32)
• Consequence: GAD2 NM_001134366.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96
• Publications: 4 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.521-772A>G		intron_variant	Intron 4 of 15	ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.521-772A>G		intron_variant	Intron 4 of 16		NP_000809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD2	ENST00000376261.8	c.521-772A>G		intron_variant	Intron 4 of 15	1	NM_001134366.2	ENSP00000365437.3
GAD2	ENST00000259271.7	c.521-772A>G		intron_variant	Intron 4 of 16	1		ENSP00000259271.3
GAD2	ENST00000648567.1	c.179-772A>G		intron_variant	Intron 4 of 16			ENSP00000498009.1
GAD2	ENST00000376248.1	n.368-772A>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18946 AN: 152142 Hom.: 1534 Cov.: 32

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.122

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.124 AC: 18953 AN: 152260 Hom.: 1540 Cov.: 32 AF XY: 0.130 AC XY: 9715 AN XY: 74450

African (AFR) AF: 0.0399 AC: 1659 AN: 41562

American (AMR) AF: 0.164 AC: 2508 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 498 AN: 3470

East Asian (EAS) AF: 0.314 AC: 1624 AN: 5176

South Asian (SAS) AF: 0.172 AC: 831 AN: 4822

European-Finnish (FIN) AF: 0.224 AC: 2375 AN: 10598

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9046 AN: 68018

Other (OTH) AF: 0.123 AC: 260 AN: 2114

Alfa AF: 0.133 Hom.: 392

Bravo AF: 0.119

Asia WGS AF: 0.214 AC: 744 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.68
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3781117; hg19: chr10-26512044;