Genetic Variant GAD1:c.547+2419T>C (chr2-170833611-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_000817.3(GAD1):c.547+2419T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 152,194 control chromosomes in the GnomAD database, including 5,057 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 0.25 ( 5057 hom., cov: 33)

Consequence

GAD1
NM_000817.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.134

Publications

13 publications found

Variant links:

Genes affected

GAD1 (HGNC:4092): (glutamate decarboxylase 1) 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 autoantigen and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Deficiency in this enzyme has been shown to lead to pyridoxine dependency with seizures. Alternative splicing of this gene results in two products, the predominant 67-kD form and a less-frequent 25-kD form. [provided by RefSeq, Jul 2008]

GAD1 Gene-Disease associations (from GenCC):

early infantile epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy 89
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
spastic quadriplegic cerebral palsy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
cerebral palsy, spastic quadriplegic, 1
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GAD1 links:

Genome browser will be placed here

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=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	NM_000817.3 link	c.547+2419T>C		intron_variant	Intron 5 of 16	ENST00000358196.8	NP_000808.2	Q99259-1A0A0S2Z3V5Q8IVA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8 link	c.547+2419T>C		intron_variant	Intron 5 of 16	1	NM_000817.3	ENSP00000350928.3		Q99259-1

Frequencies

GnomAD3 genomes

AF:

0.252

AC:

38304

AN:

152076

Hom.:

5054

Cov.:

show subpopulations

Gnomad AFR

AF:

0.312

Gnomad AMI

AF:

0.275

Gnomad AMR

AF:

0.220

Gnomad ASJ

AF:

0.319

Gnomad EAS

AF:

0.0776

Gnomad SAS

AF:

0.171

Gnomad FIN

AF:

0.251

Gnomad MID

AF:

0.310

Gnomad NFE

AF:

0.238

Gnomad OTH

AF:

0.242

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

GnomAD4 genome

AF:

0.252

AC:

38323

AN:

152194

Hom.:

5057

Cov.:

AF XY:

0.252

AC XY:

18740

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.312

AC:

12945

AN:

41496

American (AMR)

AF:

0.220

AC:

3364

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.319

AC:

1107

AN:

3472

East Asian (EAS)

AF:

0.0778

AC:

404

AN:

5192

South Asian (SAS)

AF:

0.170

AC:

823

AN:

4830

European-Finnish (FIN)

AF:

0.251

AC:

2656

AN:

10584

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.238

AC:

16175

AN:

68002

Other (OTH)

AF:

0.239

AC:

505

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1504

3008

4511

6015

7519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

392

784

1176

1568

1960

<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:

0.241

Hom.:

3356

Bravo

AF:

0.254

Asia WGS

AF:

0.138

AC:

482

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

3.7

(source)

DANN

Benign

0.49

PhyloP100

0.13

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over