10-26216567-A-G

Variant names:

• chr10-26216567-A-G
• rs2236418
• NM_000818.3:c.-243A>G

Variant summary

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

The NM_000818.3(GAD2):​c.-243A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 369,476 control chromosomes in the GnomAD database, including 20,826 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 0.36 (14906 hom., cov: 32)
  • Exomes 𝑓: 0.20 (5920 hom.)
• Consequence: GAD2 NM_000818.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.638
• Publications: 29 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 (AFR) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000818.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD2	NM_000818.3		c.-243A>G		5_prime_UTR	Exon 1 of 17	NP_000809.1
	GAD2	NM_001134366.2	MANE Select	c.-243A>G		upstream_gene	N/A	NP_001127838.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD2	ENST00000376261.8	TSL:1 MANE Select	c.-243A>G		upstream_gene	N/A	ENSP00000365437.3
	GAD2	ENST00000259271.7	TSL:1	c.-243A>G		upstream_gene	N/A	ENSP00000259271.3
	GAD2	ENST00000428517.2	TSL:1	n.-243A>G		upstream_gene	N/A	ENSP00000390434.2

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53967 AN: 151854 Hom.: 14858 Cov.: 32

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.335

GnomAD4 exome AF: 0.204 AC: 44455 AN: 217504 Hom.: 5920 Cov.: 0 AF XY: 0.204 AC XY: 23083 AN XY: 113028

African (AFR) AF: 0.769 AC: 3615 AN: 4702

American (AMR) AF: 0.261 AC: 1175 AN: 4494

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 1123 AN: 6868

East Asian (EAS) AF: 0.392 AC: 5459 AN: 13942

South Asian (SAS) AF: 0.228 AC: 3075 AN: 13514

European-Finnish (FIN) AF: 0.132 AC: 2386 AN: 18118

Middle Eastern (MID) AF: 0.292 AC: 305 AN: 1046

European-Non Finnish (NFE) AF: 0.171 AC: 24195 AN: 141194

Other (OTH) AF: 0.229 AC: 3122 AN: 13626

GnomAD4 genome AF: 0.356 AC: 54073 AN: 151972 Hom.: 14906 Cov.: 32 AF XY: 0.353 AC XY: 26224 AN XY: 74270

African (AFR) AF: 0.774 AC: 32091 AN: 41474

American (AMR) AF: 0.278 AC: 4246 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 580 AN: 3468

East Asian (EAS) AF: 0.319 AC: 1643 AN: 5156

South Asian (SAS) AF: 0.239 AC: 1146 AN: 4802

European-Finnish (FIN) AF: 0.133 AC: 1406 AN: 10556

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11954 AN: 67936

Other (OTH) AF: 0.334 AC: 705 AN: 2108

Alfa AF: 0.242 Hom.: 26192

Bravo AF: 0.387

Asia WGS AF: 0.307 AC: 1069 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.7
DANN	Benign	0.47
PhyloP100		-0.64
PromoterAI		-0.0037	Neutral
Mutation Taster		=299/1	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: rs2236418; hg19: chr10-26505496; COSMIC: COSV52164132; COSMIC: COSV52164132;