Genetic Variant NM_001134366.2:c.841-41G>T (chr10-26245880-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001134366.2(GAD2):c.841-41G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0981 in 1,457,100 control chromosomes in the GnomAD database, including 9,634 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 0.16 ( 2840 hom., cov: 32)

Exomes 𝑓: 0.091 ( 6794 hom. )

Consequence

GAD2
NM_001134366.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0990

Publications

5 publications found

Variant links:

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]

GAD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134366.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD2	NM_001134366.2	MANE Select	c.841-41G>T		intron	N/A	NP_001127838.1	Q5VZ30
	GAD2	NM_000818.3		c.841-41G>T		intron	N/A	NP_000809.1	Q05329

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GAD2	ENST00000376261.8	TSL:1 MANE Select	c.841-41G>T	intron	N/A	ENSP00000365437.3	Q05329
GAD2	ENST00000259271.7	TSL:1	c.841-41G>T	intron	N/A	ENSP00000259271.3	Q05329
GAD2	ENST00000648567.1		c.499-41G>T	intron	N/A	ENSP00000498009.1	A0A3B3IU09

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23933

AN:

152088

Hom.:

2822

Cov.:

show subpopulations

Gnomad AFR

AF:

0.338

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.0503

Gnomad SAS

AF:

0.0253

Gnomad FIN

AF:

0.0767

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0918

Gnomad OTH

AF:

0.141

GnomAD2 exomes

AF:

0.0904

AC:

21298

AN:

235622

AF XY:

0.0849

show subpopulations

Gnomad AFR exome

AF:

0.336

Gnomad AMR exome

AF:

0.0660

Gnomad ASJ exome

AF:

0.0934

Gnomad EAS exome

AF:

0.0548

Gnomad FIN exome

AF:

0.0769

Gnomad NFE exome

AF:

0.0911

Gnomad OTH exome

AF:

0.0876

GnomAD4 exome

AF:

0.0911

AC:

118937

AN:

1304894

Hom.:

6794

Cov.:

AF XY:

0.0885

AC XY:

58178

AN XY:

657250

show subpopulations

African (AFR)

AF:

0.339

AC:

10098

AN:

29792

American (AMR)

AF:

0.0719

AC:

3138

AN:

43640

Ashkenazi Jewish (ASJ)

AF:

0.0940

AC:

2354

AN:

25054

East Asian (EAS)

AF:

0.0448

AC:

1721

AN:

38402

South Asian (SAS)

AF:

0.0262

AC:

2149

AN:

82036

European-Finnish (FIN)

AF:

0.0805

AC:

4190

AN:

52068

Middle Eastern (MID)

AF:

0.0581

AC:

315

AN:

5422

European-Non Finnish (NFE)

AF:

0.0917

AC:

89286

AN:

973488

Other (OTH)

AF:

0.103

AC:

5686

AN:

54992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

4850

9700

14550

19400

24250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3100

6200

9300

12400

15500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.158

AC:

23990

AN:

152206

Hom.:

2840

Cov.:

AF XY:

0.155

AC XY:

11498

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.338

AC:

14038

AN:

41512

American (AMR)

AF:

0.116

AC:

1775

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

347

AN:

3464

East Asian (EAS)

AF:

0.0501

AC:

260

AN:

5194

South Asian (SAS)

AF:

0.0249

AC:

120

AN:

4824

European-Finnish (FIN)

AF:

0.0767

AC:

812

AN:

10588

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0917

AC:

6240

AN:

68016

Other (OTH)

AF:

0.140

AC:

295

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

950

1900

2850

3800

4750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

232

464

696

928

1160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.107

Hom.:

1513

Bravo

AF:

0.171

Asia WGS

AF:

0.0670

AC:

234

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

3.0

(source)

DANN

Benign

0.37

PhyloP100

0.099

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over