rs992990

Positions:

• chr10-26278252-C-A
• chr10-26278252-C-G
• chr10-26278252-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.1158-2757C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 152,010 control chromosomes in the GnomAD database, including 11,276 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 (11276 hom., cov: 32)
• Consequence: GAD2 NM_001134366.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00400

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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.1158-2757C>A		intron_variant		ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.1158-2757C>A		intron_variant			NP_000809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAD2	ENST00000376261.8	c.1158-2757C>A		intron_variant		1	NM_001134366.2	ENSP00000365437	P1
GAD2	ENST00000259271.7	c.1158-2757C>A		intron_variant		1		ENSP00000259271	P1
GAD2	ENST00000648567.1	c.816-2757C>A		intron_variant				ENSP00000498009

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54996 AN: 151892 Hom.: 11258 Cov.: 32

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.346

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

GnomAD4 genome AF: 0.362 AC: 55048 AN: 152010 Hom.: 11276 Cov.: 32 AF XY: 0.359 AC XY: 26649 AN XY: 74302

Gnomad4 AFR AF: 0.569

Gnomad4 AMR AF: 0.312

Gnomad4 ASJ AF: 0.283

Gnomad4 EAS AF: 0.356

Gnomad4 SAS AF: 0.280

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.346

Alfa AF: 0.179 Hom.: 345

Bravo AF: 0.380

Asia WGS AF: 0.333 AC: 1161 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.2
DANN	Benign	0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs992990; hg19: chr10-26567181;