2-170826230-C-T

Variant names:

• chr2-170826230-C-T
• rs3828275
• NM_000817.3:c.146-3245C>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.146-3245C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 151,866 control chromosomes in the GnomAD database, including 10,765 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 0.36 (10765 hom., cov: 31)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.125
• Publications: 18 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.44 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	NM_000817.3	MANE Select	c.146-3245C>T		intron	N/A	NP_000808.2
	GAD1	NM_013445.4		c.146-3245C>T		intron	N/A	NP_038473.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000358196.8	TSL:1 MANE Select	c.146-3245C>T		intron	N/A	ENSP00000350928.3
	GAD1	ENST00000375272.5	TSL:1	c.146-3245C>T		intron	N/A	ENSP00000364421.1
	GAD1	ENST00000493875.5	TSL:1	n.146-3245C>T		intron	N/A	ENSP00000434696.1

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55294 AN: 151748 Hom.: 10768 Cov.: 31

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.392

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

GnomAD4 genome AF: 0.364 AC: 55298 AN: 151866 Hom.: 10765 Cov.: 31 AF XY: 0.362 AC XY: 26858 AN XY: 74182

African (AFR) AF: 0.220 AC: 9093 AN: 41408

American (AMR) AF: 0.407 AC: 6222 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 1427 AN: 3464

East Asian (EAS) AF: 0.215 AC: 1106 AN: 5150

South Asian (SAS) AF: 0.345 AC: 1660 AN: 4810

European-Finnish (FIN) AF: 0.412 AC: 4330 AN: 10522

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.444 AC: 30136 AN: 67918

Other (OTH) AF: 0.392 AC: 827 AN: 2112

Alfa AF: 0.415 Hom.: 41900

Bravo AF: 0.358

Asia WGS AF: 0.301 AC: 1048 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.0
DANN	Benign	0.68
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: rs3828275; hg19: chr2-171682740;