rs2241165

chr2-170821869-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.83-218C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 570,728 control chromosomes in the GnomAD database, including 147,476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.63 (33071 hom., cov: 34)
  • Exomes 𝑓: 0.73 (114405 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.38

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=-0.86).
• BP6: Variant 2-170821869-C-T is Benign according to our data. Variant chr2-170821869-C-T is described in ClinVar as [Benign]. Clinvar id is 1233820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD1	NM_000817.3	c.83-218C>T		intron_variant		ENST00000358196.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD1	ENST00000358196.8	c.83-218C>T		intron_variant		1	NM_000817.3	P1

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96434 AN: 152128 Hom.: 33058 Cov.: 34

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.743

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.670

GnomAD4 exome AF: 0.735 AC: 307415 AN: 418482 Hom.: 114405 Cov.: 3 AF XY: 0.738 AC XY: 163158 AN XY: 221224

Gnomad4 AFR exome AF: 0.338

Gnomad4 AMR exome AF: 0.721

Gnomad4 ASJ exome AF: 0.668

Gnomad4 EAS exome AF: 0.700

Gnomad4 SAS exome AF: 0.764

Gnomad4 FIN exome AF: 0.745

Gnomad4 NFE exome AF: 0.758

Gnomad4 OTH exome AF: 0.708

GnomAD4 genome AF: 0.634 AC: 96472 AN: 152246 Hom.: 33071 Cov.: 34 AF XY: 0.638 AC XY: 47467 AN XY: 74430

Gnomad4 AFR AF: 0.338

Gnomad4 AMR AF: 0.725

Gnomad4 ASJ AF: 0.673

Gnomad4 EAS AF: 0.714

Gnomad4 SAS AF: 0.766

Gnomad4 FIN AF: 0.743

Gnomad4 NFE AF: 0.757

Gnomad4 OTH AF: 0.670

Alfa AF: 0.739 Hom.: 83566

Bravo AF: 0.617

Asia WGS AF: 0.736 AC: 2556 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	-0.86
Cadd	Benign	0.17
Dann	Benign	0.75

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: rs2241165; hg19: chr2-171678379; COSMIC: COSV60154465; COSMIC: COSV60154465;