2-170830049-C-T

Variant names:

• chr2-170830049-C-T
• rs2241164
• NM_000817.3:c.304+416C>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.304+416C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 151,990 control chromosomes in the GnomAD database, including 31,233 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 0.64 (31233 hom., cov: 31)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.320
• Publications: 12 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 = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	NM_000817.3	c.304+416C>T		intron_variant	Intron 4 of 16	ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8	c.304+416C>T		intron_variant	Intron 4 of 16	1	NM_000817.3	ENSP00000350928.3

Frequencies

GnomAD3 genomes AF: 0.639 AC: 97100 AN: 151870 Hom.: 31225 Cov.: 31

Gnomad AFR AF: 0.614

Gnomad AMI AF: 0.795

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.652

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

GnomAD4 genome AF: 0.639 AC: 97150 AN: 151990 Hom.: 31233 Cov.: 31 AF XY: 0.634 AC XY: 47078 AN XY: 74282

African (AFR) AF: 0.614 AC: 25441 AN: 41436

American (AMR) AF: 0.650 AC: 9927 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 2501 AN: 3470

East Asian (EAS) AF: 0.474 AC: 2445 AN: 5154

South Asian (SAS) AF: 0.489 AC: 2355 AN: 4814

European-Finnish (FIN) AF: 0.606 AC: 6399 AN: 10564

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.674 AC: 45778 AN: 67964

Other (OTH) AF: 0.649 AC: 1369 AN: 2108

Alfa AF: 0.667 Hom.: 98502

Bravo AF: 0.646

Asia WGS AF: 0.510 AC: 1776 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.36
PhyloP100		-0.32
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: rs2241164; hg19: chr2-171686559;