rs769393

Variant names:

• chr2-170853011-G-A
• rs769393
• NM_000817.3:c.1263+219G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000817.3(GAD1):​c.1263+219G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0804 in 608,614 control chromosomes in the GnomAD database, including 3,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (469 hom., cov: 32)
  • Exomes 𝑓: 0.088 (2631 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.36
• Publications: 3 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 -16 ACMG points.

• BP6: Variant 2-170853011-G-A is Benign according to our data. Variant chr2-170853011-G-A is described in ClinVar as [Benign]. Clinvar id is 1237492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	NM_000817.3	c.1263+219G>A		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+219G>A		intron_variant	Intron 13 of 16	1	NM_000817.3	ENSP00000350928.3

Frequencies

GnomAD3 genomes AF: 0.0586 AC: 8906 AN: 151990 Hom.: 468 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0452

Gnomad ASJ AF: 0.0508

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.0995

Gnomad MID AF: 0.0955

Gnomad NFE AF: 0.0610

Gnomad OTH AF: 0.0504

GnomAD4 exome AF: 0.0877 AC: 40034 AN: 456504 Hom.: 2631 Cov.: 0 AF XY: 0.0944 AC XY: 22881 AN XY: 242366

African (AFR) AF: 0.0117 AC: 147 AN: 12610

American (AMR) AF: 0.0745 AC: 1565 AN: 20994

Ashkenazi Jewish (ASJ) AF: 0.0517 AC: 736 AN: 14238

East Asian (EAS) AF: 0.223 AC: 6847 AN: 30674

South Asian (SAS) AF: 0.201 AC: 9487 AN: 47238

European-Finnish (FIN) AF: 0.0896 AC: 2702 AN: 30158

Middle Eastern (MID) AF: 0.0881 AC: 177 AN: 2008

European-Non Finnish (NFE) AF: 0.0599 AC: 16323 AN: 272384

Other (OTH) AF: 0.0782 AC: 2050 AN: 26200

GnomAD4 genome AF: 0.0586 AC: 8910 AN: 152110 Hom.: 469 Cov.: 32 AF XY: 0.0634 AC XY: 4715 AN XY: 74330

African (AFR) AF: 0.0125 AC: 519 AN: 41514

American (AMR) AF: 0.0452 AC: 690 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0508 AC: 176 AN: 3466

East Asian (EAS) AF: 0.230 AC: 1189 AN: 5160

South Asian (SAS) AF: 0.195 AC: 936 AN: 4802

European-Finnish (FIN) AF: 0.0995 AC: 1051 AN: 10566

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0610 AC: 4147 AN: 68010

Other (OTH) AF: 0.0522 AC: 110 AN: 2106

Alfa AF: 0.0673 Hom.: 183

Bravo AF: 0.0523

Asia WGS AF: 0.197 AC: 683 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

- -

Jun 20, 2021

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	-0.83
CADD	Benign	20
DANN	Benign	0.56
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs769393; hg19: chr2-171709521;