rs769406

Variant names:

• chr2-170859949-A-G
• rs769406
• ENST00000488724.5:n.952A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000488724.5(GAD1):​n.952A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,444,098 control chromosomes in the GnomAD database, including 978 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 0.025 (134 hom., cov: 32)
  • Exomes 𝑓: 0.023 (844 hom.)
• Consequence: GAD1 ENST00000488724.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.03
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	NM_000817.3	c.*67A>G		3_prime_UTR_variant	Exon 17 of 17	ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8	c.*67A>G		3_prime_UTR_variant	Exon 17 of 17	1	NM_000817.3	ENSP00000350928.3

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3742 AN: 152234 Hom.: 131 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0227

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0248

GnomAD4 exome AF: 0.0229 AC: 29643 AN: 1291746 Hom.: 844 Cov.: 18 AF XY: 0.0223 AC XY: 14455 AN XY: 647092

African (AFR) AF: 0.0137 AC: 414 AN: 30194

American (AMR) AF: 0.157 AC: 6317 AN: 40182

Ashkenazi Jewish (ASJ) AF: 0.00150 AC: 37 AN: 24748

East Asian (EAS) AF: 0.000261 AC: 10 AN: 38246

South Asian (SAS) AF: 0.0241 AC: 1914 AN: 79286

European-Finnish (FIN) AF: 0.00667 AC: 346 AN: 51902

Middle Eastern (MID) AF: 0.0118 AC: 58 AN: 4898

European-Non Finnish (NFE) AF: 0.0201 AC: 19454 AN: 967570

Other (OTH) AF: 0.0200 AC: 1093 AN: 54720

GnomAD4 genome AF: 0.0247 AC: 3757 AN: 152352 Hom.: 134 Cov.: 32 AF XY: 0.0256 AC XY: 1906 AN XY: 74500

African (AFR) AF: 0.0158 AC: 657 AN: 41586

American (AMR) AF: 0.105 AC: 1600 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0219 AC: 106 AN: 4834

European-Finnish (FIN) AF: 0.00687 AC: 73 AN: 10622

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0186 AC: 1263 AN: 68020

Other (OTH) AF: 0.0246 AC: 52 AN: 2116

Alfa AF: 0.0252 Hom.: 148

Bravo AF: 0.0317

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.029
DANN	Benign	0.26
PhyloP100		-1.0
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: rs769406; hg19: chr2-171716459;