rs769390

Variant names:

• chr2-170836945-A-C
• rs769390
• NM_000817.3:c.638+62A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-170836945-A-C
• chr2-170836945-A-G
• chr2-170836945-A-T

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.638+62A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,187,206 control chromosomes in the GnomAD database, including 41,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3868 hom., cov: 32)
  • Exomes 𝑓: 0.27 (37655 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.22
• Publications: 10 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=-0.82).
• BP6: Variant 2-170836945-A-C is Benign according to our data. Variant chr2-170836945-A-C is described in ClinVar as Benign. ClinVar VariationId is 1230108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	NM_000817.3	c.638+62A>C		intron_variant	Intron 6 of 16	ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8	c.638+62A>C		intron_variant	Intron 6 of 16	1	NM_000817.3	ENSP00000350928.3

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30665 AN: 152064 Hom.: 3865 Cov.: 32

Gnomad AFR AF: 0.0523

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.201

GnomAD4 exome AF: 0.267 AC: 276817 AN: 1035024 Hom.: 37655 AF XY: 0.272 AC XY: 144418 AN XY: 531312

African (AFR) AF: 0.0465 AC: 1161 AN: 24952

American (AMR) AF: 0.154 AC: 6345 AN: 41188

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 5018 AN: 23172

East Asian (EAS) AF: 0.272 AC: 10205 AN: 37510

South Asian (SAS) AF: 0.367 AC: 27772 AN: 75740

European-Finnish (FIN) AF: 0.313 AC: 16188 AN: 51676

Middle Eastern (MID) AF: 0.224 AC: 1116 AN: 4978

European-Non Finnish (NFE) AF: 0.271 AC: 197511 AN: 729596

Other (OTH) AF: 0.249 AC: 11501 AN: 46212

GnomAD4 genome AF: 0.202 AC: 30678 AN: 152182 Hom.: 3868 Cov.: 32 AF XY: 0.206 AC XY: 15359 AN XY: 74394

African (AFR) AF: 0.0522 AC: 2168 AN: 41554

American (AMR) AF: 0.164 AC: 2506 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 781 AN: 3472

East Asian (EAS) AF: 0.288 AC: 1493 AN: 5176

South Asian (SAS) AF: 0.368 AC: 1775 AN: 4822

European-Finnish (FIN) AF: 0.317 AC: 3347 AN: 10568

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

European-Non Finnish (NFE) AF: 0.264 AC: 17934 AN: 67988

Other (OTH) AF: 0.205 AC: 433 AN: 2114

Alfa AF: 0.218 Hom.: 527

Bravo AF: 0.181

Asia WGS AF: 0.309 AC: 1071 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	-0.82
CADD	Benign	12
DANN	Benign	0.78
PhyloP100		1.2
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: rs769390; hg19: chr2-171693455; COSMIC: COSV107424842;