chr2-170816965-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000817.3(GAD1):​c.-147G>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 0.187 in 195,752 control chromosomes in the GnomAD database, including 4,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2949 hom., cov: 31)
Exomes 𝑓: 0.22 ( 1150 hom. )

Consequence

GAD1
NM_000817.3 5_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.250
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 -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
Variant 2-170816965-G-A is Benign according to our data. Variant chr2-170816965-G-A is described in ClinVar as [Benign]. Clinvar id is 332221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-170816965-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GAD1NM_000817.3 linkuse as main transcriptc.-147G>A 5_prime_UTR_variant 1/17 ENST00000358196.8
GAD1NM_013445.4 linkuse as main transcriptc.-151G>A 5_prime_UTR_variant 1/7
GAD1XM_017003758.3 linkuse as main transcriptc.-147G>A 5_prime_UTR_variant 1/8
GAD1XM_011510922.1 linkuse as main transcriptc.-63-1564G>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GAD1ENST00000358196.8 linkuse as main transcriptc.-147G>A 5_prime_UTR_variant 1/171 NM_000817.3 P1Q99259-1
ENST00000663207.1 linkuse as main transcriptn.227C>T non_coding_transcript_exon_variant 1/2

Frequencies

GnomAD3 genomes
AF:
0.178
AC:
27101
AN:
152094
Hom.:
2949
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0443
Gnomad AMI
AF:
0.219
Gnomad AMR
AF:
0.189
Gnomad ASJ
AF:
0.260
Gnomad EAS
AF:
0.287
Gnomad SAS
AF:
0.227
Gnomad FIN
AF:
0.256
Gnomad MID
AF:
0.266
Gnomad NFE
AF:
0.228
Gnomad OTH
AF:
0.188
GnomAD4 exome
AF:
0.220
AC:
9592
AN:
43540
Hom.:
1150
Cov.:
0
AF XY:
0.225
AC XY:
5114
AN XY:
22748
show subpopulations
Gnomad4 AFR exome
AF:
0.0543
Gnomad4 AMR exome
AF:
0.195
Gnomad4 ASJ exome
AF:
0.262
Gnomad4 EAS exome
AF:
0.279
Gnomad4 SAS exome
AF:
0.214
Gnomad4 FIN exome
AF:
0.245
Gnomad4 NFE exome
AF:
0.214
Gnomad4 OTH exome
AF:
0.192
GnomAD4 genome
AF:
0.178
AC:
27099
AN:
152212
Hom.:
2949
Cov.:
31
AF XY:
0.182
AC XY:
13515
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.0442
Gnomad4 AMR
AF:
0.189
Gnomad4 ASJ
AF:
0.260
Gnomad4 EAS
AF:
0.287
Gnomad4 SAS
AF:
0.225
Gnomad4 FIN
AF:
0.256
Gnomad4 NFE
AF:
0.228
Gnomad4 OTH
AF:
0.189
Alfa
AF:
0.215
Hom.:
5017
Bravo
AF:
0.167
Asia WGS
AF:
0.217
AC:
755
AN:
3476

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 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 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
-0.43
CADD
Benign
15
DANN
Benign
0.94

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: rs3749034; hg19: chr2-171673475; API