chr2-170816857-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

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

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.639
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
GAD1XM_011510922.1 linkuse as main transcriptc.-63-1672G>A intron_variant
GAD1NM_000817.3 linkuse as main transcript upstream_gene_variant ENST00000358196.8
GAD1NM_013445.4 linkuse as main transcript upstream_gene_variant
GAD1XM_017003758.3 linkuse as main transcript upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ENST00000663207.1 linkuse as main transcriptn.335C>T non_coding_transcript_exon_variant 1/2
GAD1ENST00000358196.8 linkuse as main transcript upstream_gene_variant 1 NM_000817.3 P1Q99259-1

Frequencies

GnomAD3 genomes
AF:
0.00348
AC:
520
AN:
149304
Hom.:
1
Cov.:
31
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs545676026; hg19: chr2-171673367; API