2-170860293-G-A

Variant names:

• chr2-170860293-G-A
• rs769395
• ENST00000493875.5:n.*1030G>A

Variant summary

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

The ENST00000493875.5(GAD1):​n.*1030G>A 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 0.755 in 185,014 control chromosomes in the GnomAD database, including 53,094 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 0.76 (43988 hom., cov: 32)
  • Exomes 𝑓: 0.73 (9106 hom.)
• Consequence: GAD1 ENST00000493875.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278
• Publications: 16 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000493875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	NM_000817.3	MANE Select	c.*411G>A		3_prime_UTR	Exon 17 of 17	NP_000808.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000493875.5	TSL:1	n.*1030G>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000434696.1
	GAD1	ENST00000358196.8	TSL:1 MANE Select	c.*411G>A		3_prime_UTR	Exon 17 of 17	ENSP00000350928.3
	GAD1	ENST00000493875.5	TSL:1	n.*1030G>A		3_prime_UTR	Exon 17 of 17	ENSP00000434696.1

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115381 AN: 151950 Hom.: 43952 Cov.: 32

Gnomad AFR AF: 0.819

Gnomad AMI AF: 0.807

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.753

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.683

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.737

Gnomad OTH AF: 0.773

GnomAD4 exome AF: 0.734 AC: 24167 AN: 32946 Hom.: 9106 Cov.: 0 AF XY: 0.727 AC XY: 12819 AN XY: 17632

African (AFR) AF: 0.821 AC: 632 AN: 770

American (AMR) AF: 0.821 AC: 2468 AN: 3006

Ashkenazi Jewish (ASJ) AF: 0.780 AC: 582 AN: 746

East Asian (EAS) AF: 0.686 AC: 1340 AN: 1954

South Asian (SAS) AF: 0.647 AC: 2963 AN: 4580

European-Finnish (FIN) AF: 0.684 AC: 967 AN: 1414

Middle Eastern (MID) AF: 0.796 AC: 78 AN: 98

European-Non Finnish (NFE) AF: 0.742 AC: 14050 AN: 18946

Other (OTH) AF: 0.759 AC: 1087 AN: 1432

GnomAD4 genome AF: 0.759 AC: 115472 AN: 152068 Hom.: 43988 Cov.: 32 AF XY: 0.755 AC XY: 56109 AN XY: 74318

African (AFR) AF: 0.819 AC: 33955 AN: 41474

American (AMR) AF: 0.812 AC: 12420 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.753 AC: 2613 AN: 3468

East Asian (EAS) AF: 0.679 AC: 3504 AN: 5160

South Asian (SAS) AF: 0.637 AC: 3067 AN: 4814

European-Finnish (FIN) AF: 0.683 AC: 7218 AN: 10562

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.737 AC: 50120 AN: 67984

Other (OTH) AF: 0.770 AC: 1625 AN: 2110

Alfa AF: 0.751 Hom.: 61260

Bravo AF: 0.773

Asia WGS AF: 0.673 AC: 2342 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.4
DANN	Benign	0.83
PhyloP100		0.28
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: rs769395; hg19: chr2-171716803;