2-170818551-C-CCT

Position:

• chr2-170818551-C-CCT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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]

ACMG classification

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
GAD1	NM_000817.3	c.-41_-40insCT		5_prime_UTR_variant	2/17	ENST00000358196.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD1	ENST00000358196.8	c.-41_-40insCT		5_prime_UTR_variant	2/17	1	NM_000817.3	P1

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152178 Hom.: 1 Cov.: 31

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

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

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

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

Submissions by phenotype

Cerebral palsy spastic quadriplegic Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs560889153; hg19: chr2-171675061;