2-170816954-G-A

Variant names:

• chr2-170816954-G-A
• rs45486908
• ENST00000358196:c.-158G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_000817.3(GAD1):​c.-158G>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 0.0197 in 195,242 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (136 hom., cov: 31)
  • Exomes 𝑓: 0.014 (14 hom.)
• Consequence: GAD1 NM_000817.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.150

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]

ENSG00000235934 (HGNC:40250):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-170816954-G-A is Benign according to our data. Variant chr2-170816954-G-A is described in ClinVar as [Benign]. Clinvar id is 332220.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	NM_000817.3	c.-158G>A		5_prime_UTR_variant	Exon 1 of 17	ENST00000358196.8	NP_000808.2
GAD1	NM_013445.4	c.-162G>A		5_prime_UTR_variant	Exon 1 of 7		NP_038473.2
GAD1	XM_017003758.3	c.-158G>A		5_prime_UTR_variant	Exon 1 of 8		XP_016859247.1
GAD1	XM_011510922.1	c.-63-1575G>A		intron_variant	Intron 1 of 16		XP_011509224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196	c.-158G>A		5_prime_UTR_variant	Exon 1 of 17	1	NM_000817.3	ENSP00000350928.3

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3230 AN: 152188 Hom.: 133 Cov.: 31

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.0141 AC: 607 AN: 42936 Hom.: 14 Cov.: 0 AF XY: 0.0147 AC XY: 331 AN XY: 22456

Gnomad4 AFR exome AF: 0.00288

Gnomad4 AMR exome AF: 0.0936

Gnomad4 ASJ exome AF: 0.00152

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.00665

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome AF: 0.0213 AC: 3240 AN: 152306 Hom.: 136 Cov.: 31 AF XY: 0.0224 AC XY: 1671 AN XY: 74470

Gnomad4 AFR AF: 0.00558

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.00687

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0196 Hom.: 7

Bravo AF: 0.0279

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
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: rs45486908; hg19: chr2-171673464;