2-170818186-T-C

Position:

• chr2-170818186-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000817.3(GAD1):​c.-63-343T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 219,122 control chromosomes in the GnomAD database, including 51,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (33037 hom., cov: 28)
  • Exomes 𝑓: 0.73 (18799 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.297

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-170818186-T-C is Benign according to our data. Variant chr2-170818186-T-C is described in ClinVar as [Benign]. Clinvar id is 1233523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD1	NM_000817.3	c.-63-343T>C		intron_variant		ENST00000358196.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD1	ENST00000358196.8	c.-63-343T>C		intron_variant		1	NM_000817.3	P1

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96435 AN: 151080 Hom.: 33025 Cov.: 28

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.767

Gnomad FIN AF: 0.741

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.756

Gnomad OTH AF: 0.676

GnomAD4 exome AF: 0.728 AC: 49457 AN: 67930 Hom.: 18799 Cov.: 0 AF XY: 0.732 AC XY: 26367 AN XY: 36030

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.728

Gnomad4 ASJ exome AF: 0.635

Gnomad4 EAS exome AF: 0.695

Gnomad4 SAS exome AF: 0.767

Gnomad4 FIN exome AF: 0.725

Gnomad4 NFE exome AF: 0.751

Gnomad4 OTH exome AF: 0.701

GnomAD4 genome AF: 0.638 AC: 96471 AN: 151192 Hom.: 33037 Cov.: 28 AF XY: 0.642 AC XY: 47405 AN XY: 73824

Gnomad4 AFR AF: 0.354

Gnomad4 AMR AF: 0.727

Gnomad4 ASJ AF: 0.673

Gnomad4 EAS AF: 0.716

Gnomad4 SAS AF: 0.769

Gnomad4 FIN AF: 0.741

Gnomad4 NFE AF: 0.756

Gnomad4 OTH AF: 0.676

Alfa AF: 0.679 Hom.: 4583

Bravo AF: 0.621

Asia WGS AF: 0.737 AC: 2553 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.3
DANN	Benign	0.64

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

Other links and lift over

dbSNP: rs2270335; hg19: chr2-171674696;