10-26278252-C-A

Variant names:

• chr10-26278252-C-A
• rs992990
• NM_001134366.2:c.1158-2757C>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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=-0.95).
• 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 rank	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.1158-2757C>A		intron_variant	Intron 11 of 15	ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.1158-2757C>A		intron_variant	Intron 11 of 16		NP_000809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD2	ENST00000376261.8	c.1158-2757C>A		intron_variant	Intron 11 of 15	1	NM_001134366.2	ENSP00000365437.3
GAD2	ENST00000259271.7	c.1158-2757C>A		intron_variant	Intron 11 of 16	1		ENSP00000259271.3
GAD2	ENST00000648567.1	c.816-2757C>A		intron_variant	Intron 11 of 16			ENSP00000498009.1

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

African (AFR) AF: 0.569 AC: 23590 AN: 41434

American (AMR) AF: 0.312 AC: 4772 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 984 AN: 3472

East Asian (EAS) AF: 0.356 AC: 1840 AN: 5164

South Asian (SAS) AF: 0.280 AC: 1348 AN: 4812

European-Finnish (FIN) AF: 0.219 AC: 2306 AN: 10548

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19068 AN: 67978

Other (OTH) AF: 0.346 AC: 731 AN: 2110

Alfa AF: 0.200 Hom.: 471

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
PhyloP100		0.0040
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: rs992990; hg19: chr10-26567181;