10-26270630-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001134366.2(GAD2):c.976-10G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,598,540 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (14 hom.)
• Consequence: GAD2 NM_001134366.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001562
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.31

Genes affected

GAD2 (HGNC:4093): (glutamate decarboxylase 2) 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 autoantibody and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 10-26270630-G-A is Benign according to our data. Variant chr10-26270630-G-A is described in ClinVar as [Benign]. Clinvar id is 788279.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 384 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD2	NM_001134366.2	c.976-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000376261.8
GAD2	NM_000818.3	c.976-10G>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD2	ENST00000376261.8	c.976-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001134366.2	P1
GAD2	ENST00000259271.7	c.976-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1		P1
GAD2	ENST00000648567.1	c.634-10G>A		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 384 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00541

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00219 AC: 550 AN: 250808 Hom.: 5 AF XY: 0.00227 AC XY: 308 AN XY: 135532

Gnomad AFR exome AF: 0.00585

Gnomad AMR exome AF: 0.00273

Gnomad ASJ exome AF: 0.00696

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00469

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000987

Gnomad OTH exome AF: 0.00588

GnomAD4 exome AF: 0.00112 AC: 1627 AN: 1446284 Hom.: 14 Cov.: 27 AF XY: 0.00130 AC XY: 938 AN XY: 720530

Gnomad4 AFR exome AF: 0.00488

Gnomad4 AMR exome AF: 0.00289

Gnomad4 ASJ exome AF: 0.00707

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00414

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000516

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.00227 AC XY: 169 AN XY: 74436

Gnomad4 AFR AF: 0.00541

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00333

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00277 Hom.: 4

Bravo AF: 0.00297

Asia WGS AF: 0.00115 AC: 4 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

Invitae

Aug 18, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.0020
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.038
SpliceAI score (max)		0.010		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: rs74767822; hg19: chr10-26559559;