2-170815568-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000663207.1(ENSG00000235934):n.1256G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 152,002 control chromosomes in the GnomAD database, including 6,993 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 0.28 (6993 hom., cov: 31)
• Consequence: ENST00000663207.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.409

Genes affected

(HGNC:):

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD1	XM_011510922.1	c.-64+2146C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000663207.1	n.1256G>C		non_coding_transcript_exon_variant	2/2
GAD1	ENST00000454603.5	c.-64+2146C>G		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43205 AN: 151884 Hom.: 6985 Cov.: 31

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.304

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

GnomAD4 genome AF: 0.285 AC: 43245 AN: 152002 Hom.: 6993 Cov.: 31 AF XY: 0.288 AC XY: 21413 AN XY: 74298

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.352

Gnomad4 ASJ AF: 0.294

Gnomad4 EAS AF: 0.503

Gnomad4 SAS AF: 0.391

Gnomad4 FIN AF: 0.337

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.304

Alfa AF: 0.174 Hom.: 390

Bravo AF: 0.279

Asia WGS AF: 0.429 AC: 1486 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.75
Dann	Benign	0.60

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3762556; hg19: chr2-171672078;