rs12185692

Variant names:

• chr2-170814316-C-A
• rs12185692
• ENST00000454603.5:c.-64+894C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000454603.5(GAD1):​c.-64+894C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 151,814 control chromosomes in the GnomAD database, including 9,164 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (9164 hom., cov: 31)
• Consequence: GAD1 ENST00000454603.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.12
• Publications: 7 publications found

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]

ERICH2-DT (HGNC:55686): (ERICH2 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	XM_011510922.1	c.-64+894C>A		intron_variant	Intron 1 of 16		XP_011509224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000454603.5	c.-64+894C>A		intron_variant	Intron 1 of 3	4		ENSP00000402366.1
ERICH2-DT	ENST00000728834.1	n.358+2538G>T		intron_variant	Intron 1 of 4
ERICH2-DT	ENST00000728835.1	n.338+2538G>T		intron_variant	Intron 1 of 5

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50190 AN: 151696 Hom.: 9168 Cov.: 31

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.418

Gnomad OTH AF: 0.356

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

GnomAD4 genome AF: 0.331 AC: 50186 AN: 151814 Hom.: 9164 Cov.: 31 AF XY: 0.330 AC XY: 24505 AN XY: 74154

African (AFR) AF: 0.166 AC: 6858 AN: 41408

American (AMR) AF: 0.360 AC: 5482 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1388 AN: 3466

East Asian (EAS) AF: 0.209 AC: 1076 AN: 5142

South Asian (SAS) AF: 0.319 AC: 1536 AN: 4808

European-Finnish (FIN) AF: 0.403 AC: 4235 AN: 10518

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.418 AC: 28378 AN: 67908

Other (OTH) AF: 0.356 AC: 752 AN: 2114

Alfa AF: 0.387 Hom.: 2448

Bravo AF: 0.320

Asia WGS AF: 0.283 AC: 986 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.069
DANN	Benign	0.69
PhyloP100		-4.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12185692; hg19: chr2-171670826;