chr2-170816965-G-A
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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
NM_000817.3 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.250
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]
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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 |
---|---|---|---|---|---|---|---|
GAD1 | NM_000817.3 | c.-147G>A | 5_prime_UTR_variant | 1/17 | ENST00000358196.8 | ||
GAD1 | NM_013445.4 | c.-151G>A | 5_prime_UTR_variant | 1/7 | |||
GAD1 | XM_017003758.3 | c.-147G>A | 5_prime_UTR_variant | 1/8 | |||
GAD1 | XM_011510922.1 | c.-63-1564G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAD1 | ENST00000358196.8 | c.-147G>A | 5_prime_UTR_variant | 1/17 | 1 | NM_000817.3 | P1 | ||
ENST00000663207.1 | n.227C>T | non_coding_transcript_exon_variant | 1/2 |
Frequencies
GnomAD3 genomes AF: 0.178 AC: 27101AN: 152094Hom.: 2949 Cov.: 31
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GnomAD4 exome AF: 0.220 AC: 9592AN: 43540Hom.: 1150 Cov.: 0 AF XY: 0.225 AC XY: 5114AN XY: 22748
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GnomAD4 genome AF: 0.178 AC: 27099AN: 152212Hom.: 2949 Cov.: 31 AF XY: 0.182 AC XY: 13515AN XY: 74416
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ClinVar
Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:1
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 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 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
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at