2-170816857-G-A

Position:

• chr2-170816857-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The ENST00000375272.5(GAD1):​c.-259G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 150,710 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 31)
  • Exomes 𝑓: 0.010 (2 hom.)
• Consequence: GAD1 ENST00000375272.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.639

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00348 (520/149444) while in subpopulation NFE AF= 0.00572 (385/67256). AF 95% confidence interval is 0.00525. There are 1 homozygotes in gnomad4. There are 235 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD1	XM_011510922.1	c.-63-1672G>A		intron_variant
GAD1	NM_000817.3			upstream_gene_variant		ENST00000358196.8
GAD1	NM_013445.4			upstream_gene_variant
GAD1	XM_017003758.3			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000663207.1	n.335C>T		non_coding_transcript_exon_variant	1/2
GAD1	ENST00000358196.8			upstream_gene_variant		1	NM_000817.3	P1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 520 AN: 149304 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00108

Gnomad AMI AF: 0.0434

Gnomad AMR AF: 0.00147

Gnomad ASJ AF: 0.00463

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000675

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.00340

GnomAD4 exome AF: 0.0103 AC: 13 AN: 1266 Hom.: 2 Cov.: 0 AF XY: 0.0106 AC XY: 7 AN XY: 662

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.00348 AC: 520 AN: 149444 Hom.: 1 Cov.: 31 AF XY: 0.00322 AC XY: 235 AN XY: 73010

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00147

Gnomad4 ASJ AF: 0.00463

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000675

Gnomad4 NFE AF: 0.00572

Gnomad4 OTH AF: 0.00337

Alfa AF: 0.00444 Hom.: 0

Bravo AF: 0.00361

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.0
DANN	Benign	0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs545676026; hg19: chr2-171673367;