2-170818186-T-C

Variant names:

• chr2-170818186-T-C
• rs2270335
• NM_000817.3:c.-63-343T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000817.3(GAD1):​c.-63-343T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 219,122 control chromosomes in the GnomAD database, including 51,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (33037 hom., cov: 28)
  • Exomes 𝑓: 0.73 (18799 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.297
• Publications: 8 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]

GAD1-AS1 (HGNC:40250):

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-170818186-T-C is Benign according to our data. Variant chr2-170818186-T-C is described in ClinVar as Benign. ClinVar VariationId is 1233523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000817.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	NM_000817.3	MANE Select	c.-63-343T>C		intron	N/A	NP_000808.2	Q99259-1
	GAD1	NM_013445.4		c.-63-343T>C		intron	N/A	NP_038473.2
	GAD1-AS1	NR_197761.1		n.266+200A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000358196.8	TSL:1 MANE Select	c.-63-343T>C		intron	N/A	ENSP00000350928.3	Q99259-1
	GAD1	ENST00000375272.5	TSL:1	c.-63-343T>C		intron	N/A	ENSP00000364421.1	Q99259-3
	GAD1	ENST00000493875.5	TSL:1	n.-406T>C		non_coding_transcript_exon	Exon 1 of 17	ENSP00000434696.1	Q99259-4

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96435 AN: 151080 Hom.: 33025 Cov.: 28

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.767

Gnomad FIN AF: 0.741

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.756

Gnomad OTH AF: 0.676

GnomAD4 exome AF: 0.728 AC: 49457 AN: 67930 Hom.: 18799 Cov.: 0 AF XY: 0.732 AC XY: 26367 AN XY: 36030

African (AFR) AF: 0.313 AC: 716 AN: 2284

American (AMR) AF: 0.728 AC: 2810 AN: 3860

Ashkenazi Jewish (ASJ) AF: 0.635 AC: 1018 AN: 1602

East Asian (EAS) AF: 0.695 AC: 1978 AN: 2848

South Asian (SAS) AF: 0.767 AC: 7467 AN: 9738

European-Finnish (FIN) AF: 0.725 AC: 2144 AN: 2956

Middle Eastern (MID) AF: 0.698 AC: 169 AN: 242

European-Non Finnish (NFE) AF: 0.751 AC: 30634 AN: 40802

Other (OTH) AF: 0.701 AC: 2521 AN: 3598

GnomAD4 genome AF: 0.638 AC: 96471 AN: 151192 Hom.: 33037 Cov.: 28 AF XY: 0.642 AC XY: 47405 AN XY: 73824

African (AFR) AF: 0.354 AC: 14543 AN: 41092

American (AMR) AF: 0.727 AC: 11083 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2333 AN: 3466

East Asian (EAS) AF: 0.716 AC: 3602 AN: 5030

South Asian (SAS) AF: 0.769 AC: 3671 AN: 4772

European-Finnish (FIN) AF: 0.741 AC: 7750 AN: 10452

Middle Eastern (MID) AF: 0.586 AC: 171 AN: 292

European-Non Finnish (NFE) AF: 0.756 AC: 51270 AN: 67830

Other (OTH) AF: 0.676 AC: 1422 AN: 2104

Alfa AF: 0.679 Hom.: 4583

Bravo AF: 0.621

Asia WGS AF: 0.737 AC: 2553 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.3
DANN	Benign	0.64
PhyloP100		0.30
PromoterAI		0.0051	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2270335; hg19: chr2-171674696;