chr2-170858623-C-G

Position:

• chr2-170858623-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.1522-181C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 152,004 control chromosomes in the GnomAD database, including 5,095 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.25 (5095 hom., cov: 32)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.392

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]

GAD1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-170858623-C-G is Benign according to our data. Variant chr2-170858623-C-G is described in ClinVar as [Benign]. Clinvar id is 1293424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAD1	NM_000817.3	c.1522-181C>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.1522-181C>G		intron_variant		1	NM_000817.3	ENSP00000350928.3

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37864 AN: 151886 Hom.: 5090 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.247

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.249 AC: 37914 AN: 152004 Hom.: 5095 Cov.: 32 AF XY: 0.255 AC XY: 18918 AN XY: 74274

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.320

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.325

Gnomad4 NFE AF: 0.283

Gnomad4 OTH AF: 0.250

Alfa AF: 0.258 Hom.: 650

Bravo AF: 0.240

Asia WGS AF: 0.344 AC: 1194 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.8
DANN	Benign	0.50

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: rs7578661; hg19: chr2-171715133; COSMIC: COSV64025249;