rs3781118

Variant names:

• chr10-26220185-A-C
• rs3781118
• NM_001134366.2:c.520+909A>C

Variant summary

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

The NM_001134366.2(GAD2):​c.520+909A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.061 in 152,228 control chromosomes in the GnomAD database, including 361 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 0.061 (361 hom., cov: 32)
• Consequence: GAD2 NM_001134366.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• Publications: 1 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=-0.59).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.520+909A>C		intron_variant	Intron 4 of 15	ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.520+909A>C		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.520+909A>C		intron_variant	Intron 4 of 15	1	NM_001134366.2	ENSP00000365437.3
GAD2	ENST00000259271.7	c.520+909A>C		intron_variant	Intron 4 of 16	1		ENSP00000259271.3
GAD2	ENST00000648567.1	c.178+909A>C		intron_variant	Intron 4 of 16			ENSP00000498009.1
GAD2	ENST00000376248.1	n.367+909A>C		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0611 AC: 9300 AN: 152110 Hom.: 361 Cov.: 32

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0738

Gnomad ASJ AF: 0.0991

Gnomad EAS AF: 0.0504

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.0703

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0853

Gnomad OTH AF: 0.0681

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

GnomAD4 genome AF: 0.0610 AC: 9293 AN: 152228 Hom.: 361 Cov.: 32 AF XY: 0.0602 AC XY: 4480 AN XY: 74434

African (AFR) AF: 0.0173 AC: 719 AN: 41552

American (AMR) AF: 0.0737 AC: 1127 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0991 AC: 344 AN: 3470

East Asian (EAS) AF: 0.0503 AC: 261 AN: 5186

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4828

European-Finnish (FIN) AF: 0.0703 AC: 745 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0853 AC: 5798 AN: 67990

Other (OTH) AF: 0.0674 AC: 142 AN: 2108

Alfa AF: 0.0706 Hom.: 43

Bravo AF: 0.0615

Asia WGS AF: 0.0450 AC: 158 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.64
PhyloP100		1.1
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: rs3781118; hg19: chr10-26509114;