2-170833210-G-T

Variant names:

• chr2-170833210-G-T
• rs3791858
• NM_000817.3:c.547+2018G>T

Variant summary

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

The NM_000817.3(GAD1):​c.547+2018G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,162 control chromosomes in the GnomAD database, including 4,102 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 0.23 (4102 hom., cov: 33)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.133
• Publications: 5 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.63).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000817.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	NM_000817.3	MANE Select	c.547+2018G>T		intron	N/A	NP_000808.2	Q99259-1
	GAD1	NM_013445.4		c.547+2018G>T		intron	N/A	NP_038473.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000358196.8	TSL:1 MANE Select	c.547+2018G>T		intron	N/A	ENSP00000350928.3	Q99259-1
	GAD1	ENST00000375272.5	TSL:1	c.547+2018G>T		intron	N/A	ENSP00000364421.1	Q99259-3
	GAD1	ENST00000493875.5	TSL:1	n.547+2018G>T		intron	N/A	ENSP00000434696.1	Q99259-4

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34476 AN: 152044 Hom.: 4091 Cov.: 33

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.200

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.227 AC: 34527 AN: 152162 Hom.: 4102 Cov.: 33 AF XY: 0.229 AC XY: 17060 AN XY: 74376

African (AFR) AF: 0.231 AC: 9592 AN: 41508

American (AMR) AF: 0.144 AC: 2208 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 665 AN: 3468

East Asian (EAS) AF: 0.232 AC: 1203 AN: 5178

South Asian (SAS) AF: 0.339 AC: 1637 AN: 4828

European-Finnish (FIN) AF: 0.301 AC: 3186 AN: 10576

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15392 AN: 68002

Other (OTH) AF: 0.204 AC: 431 AN: 2108

Alfa AF: 0.170 Hom.: 554

Bravo AF: 0.214

Asia WGS AF: 0.284 AC: 985 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.83
PhyloP100		0.13
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: rs3791858; hg19: chr2-171689720;