NM_000817.3:c.1263+128A>G

Variant names:

• chr2-170852920-A-G
• rs769391
• NM_000817.3:c.1263+128A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000817.3(GAD1):​c.1263+128A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 767,180 control chromosomes in the GnomAD database, including 33,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6321 hom., cov: 32)
  • Exomes 𝑓: 0.28 (26721 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.329
• Publications: 7 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-170852920-A-G is Benign according to our data. Variant chr2-170852920-A-G is described in ClinVar as Benign. ClinVar VariationId is 1265514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	NM_000817.3	c.1263+128A>G		intron_variant	Intron 13 of 16	ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8	c.1263+128A>G		intron_variant	Intron 13 of 16	1	NM_000817.3	ENSP00000350928.3

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43611 AN: 151836 Hom.: 6305 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.272

GnomAD4 exome AF: 0.285 AC: 175222 AN: 615224 Hom.: 26721 Cov.: 7 AF XY: 0.290 AC XY: 95390 AN XY: 329114

African (AFR) AF: 0.266 AC: 4512 AN: 16958

American (AMR) AF: 0.321 AC: 11198 AN: 34936

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 4469 AN: 20308

East Asian (EAS) AF: 0.297 AC: 9701 AN: 32690

South Asian (SAS) AF: 0.378 AC: 23955 AN: 63400

European-Finnish (FIN) AF: 0.314 AC: 14337 AN: 45668

Middle Eastern (MID) AF: 0.225 AC: 706 AN: 3140

European-Non Finnish (NFE) AF: 0.267 AC: 97552 AN: 365778

Other (OTH) AF: 0.272 AC: 8792 AN: 32346

GnomAD4 genome AF: 0.287 AC: 43681 AN: 151956 Hom.: 6321 Cov.: 32 AF XY: 0.291 AC XY: 21571 AN XY: 74254

African (AFR) AF: 0.274 AC: 11360 AN: 41434

American (AMR) AF: 0.296 AC: 4523 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 811 AN: 3466

East Asian (EAS) AF: 0.316 AC: 1630 AN: 5156

South Asian (SAS) AF: 0.386 AC: 1857 AN: 4816

European-Finnish (FIN) AF: 0.323 AC: 3410 AN: 10544

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.284 AC: 19271 AN: 67950

Other (OTH) AF: 0.275 AC: 580 AN: 2112

Alfa AF: 0.280 Hom.: 947

Bravo AF: 0.284

Asia WGS AF: 0.349 AC: 1211 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.68
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs769391; hg19: chr2-171709430; COSMIC: COSV107450114;