2-170845254-C-G

Position:

• chr2-170845254-C-G

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.752-252C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 547,186 control chromosomes in the GnomAD database, including 28,562 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7489 hom., cov: 32)
  • Exomes 𝑓: 0.32 (21073 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.77

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 2-170845254-C-G is Benign according to our data. Variant chr2-170845254-C-G is described in ClinVar as [Benign]. Clinvar id is 1277575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAD1	NM_000817.3	c.752-252C>G		intron_variant		ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8	c.752-252C>G		intron_variant		1	NM_000817.3	ENSP00000350928	P1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47051 AN: 151902 Hom.: 7468 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.303

GnomAD4 exome AF: 0.317 AC: 125413 AN: 395166 Hom.: 21073 AF XY: 0.323 AC XY: 67795 AN XY: 210094

Gnomad4 AFR exome AF: 0.310

Gnomad4 AMR exome AF: 0.328

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.482

Gnomad4 SAS exome AF: 0.408

Gnomad4 FIN exome AF: 0.327

Gnomad4 NFE exome AF: 0.287

Gnomad4 OTH exome AF: 0.302

GnomAD4 genome AF: 0.310 AC: 47127 AN: 152020 Hom.: 7489 Cov.: 32 AF XY: 0.314 AC XY: 23355 AN XY: 74290

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.320

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.533

Gnomad4 SAS AF: 0.425

Gnomad4 FIN AF: 0.329

Gnomad4 NFE AF: 0.289

Gnomad4 OTH AF: 0.306

Alfa AF: 0.164 Hom.: 323

Bravo AF: 0.308

Asia WGS AF: 0.460 AC: 1597 AN: 3478

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	clinical testing	GeneDx	Jun 18, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	11
DANN	Benign	0.55

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: rs16858977; hg19: chr2-171701764;