rs701492

chr2-170845970-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000817.3(GAD1):c.948-39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 1,578,180 control chromosomes in the GnomAD database, including 67,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6075 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61605 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.782

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-170845970-C-T is Benign according to our data. Variant chr2-170845970-C-T is described in ClinVar as [Benign]. Clinvar id is 1260220.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD1	NM_000817.3	c.948-39C>T		intron_variant		ENST00000358196.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD1	ENST00000358196.8	c.948-39C>T		intron_variant		1	NM_000817.3	P1
GAD1	ENST00000493875.5	c.948-39C>T		intron_variant, NMD_transcript_variant		1
GAD1	ENST00000625689.2	c.948-39C>T		intron_variant		5
GAD1	ENST00000414527.6	c.*133-39C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42706 AN: 151876 Hom.: 6059 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.268

GnomAD3 exomes AF: 0.297 AC: 74389 AN: 250060 Hom.: 11509 AF XY: 0.300 AC XY: 40667 AN XY: 135572

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.284

Gnomad SAS exome AF: 0.382

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.291 AC: 414352 AN: 1426186 Hom.: 61605 Cov.: 25 AF XY: 0.292 AC XY: 207817 AN XY: 711794

Gnomad4 AFR exome AF: 0.258

Gnomad4 AMR exome AF: 0.324

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.287

Gnomad4 SAS exome AF: 0.381

Gnomad4 FIN exome AF: 0.319

Gnomad4 NFE exome AF: 0.284

Gnomad4 OTH exome AF: 0.279

GnomAD4 genome AF: 0.281 AC: 42774 AN: 151994 Hom.: 6075 Cov.: 32 AF XY: 0.284 AC XY: 21115 AN XY: 74266

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.226

Gnomad4 EAS AF: 0.295

Gnomad4 SAS AF: 0.384

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.283

Gnomad4 OTH AF: 0.271

Alfa AF: 0.280 Hom.: 12520

Bravo AF: 0.277

Asia WGS AF: 0.343 AC: 1191 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.80
Cadd	Benign	15
Dann	Benign	0.49

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: rs701492; hg19: chr2-171702480; COSMIC: COSV60151788; COSMIC: COSV60151788;