chr2-170818551-C-CCT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_000817.3(GAD1):​c.-41_-40insCT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,578,956 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 31)
Exomes 𝑓: 0.0027 ( 7 hom. )

Consequence

GAD1
NM_000817.3 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.24
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 Likely_benign. Variant got -5 ACMG points.

BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0021 (320/152296) while in subpopulation NFE AF= 0.0035 (238/68028). AF 95% confidence interval is 0.00313. There are 1 homozygotes in gnomad4. There are 162 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 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GAD1NM_000817.3 linkuse as main transcriptc.-41_-40insCT 5_prime_UTR_variant 2/17 ENST00000358196.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GAD1ENST00000358196.8 linkuse as main transcriptc.-41_-40insCT 5_prime_UTR_variant 2/171 NM_000817.3 P1Q99259-1

Frequencies

GnomAD3 genomes
AF:
0.00210
AC:
320
AN:
152178
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00183
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00254
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00350
Gnomad OTH
AF:
0.00478
GnomAD3 exomes
AF:
0.00250
AC:
628
AN:
250954
Hom.:
1
AF XY:
0.00225
AC XY:
305
AN XY:
135734
show subpopulations
Gnomad AFR exome
AF:
0.000555
Gnomad AMR exome
AF:
0.00272
Gnomad ASJ exome
AF:
0.000596
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00245
Gnomad NFE exome
AF:
0.00394
Gnomad OTH exome
AF:
0.00294
GnomAD4 exome
AF:
0.00269
AC:
3841
AN:
1426660
Hom.:
7
Cov.:
26
AF XY:
0.00267
AC XY:
1902
AN XY:
712072
show subpopulations
Gnomad4 AFR exome
AF:
0.000274
Gnomad4 AMR exome
AF:
0.00262
Gnomad4 ASJ exome
AF:
0.000617
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000234
Gnomad4 FIN exome
AF:
0.00390
Gnomad4 NFE exome
AF:
0.00313
Gnomad4 OTH exome
AF:
0.00177
GnomAD4 genome
AF:
0.00210
AC:
320
AN:
152296
Hom.:
1
Cov.:
31
AF XY:
0.00218
AC XY:
162
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.000313
Gnomad4 AMR
AF:
0.00183
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00254
Gnomad4 NFE
AF:
0.00350
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.00372
Hom.:
0
Bravo
AF:
0.00203

ClinVar

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

Submissions by phenotype

Cerebral palsy spastic quadriplegic Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs560889153; hg19: chr2-171675061; API