rs2839673

Positions:

• chr10-26224622-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001134366.2(GAD2):​c.695G>A​(p.Gly232Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00782 in 1,613,388 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0059 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (69 hom.)
• Consequence: GAD2 NM_001134366.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.27

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]

GAD2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071927905).
• BP6: Variant 10-26224622-G-A is Benign according to our data. Variant chr10-26224622-G-A is described in ClinVar as [Benign]. Clinvar id is 774469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 898 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.695G>A	p.Gly232Glu	missense_variant	6/16	ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.695G>A	p.Gly232Glu	missense_variant	6/17		NP_000809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAD2	ENST00000376261.8	c.695G>A	p.Gly232Glu	missense_variant	6/16	1	NM_001134366.2	ENSP00000365437.3
GAD2	ENST00000259271.7	c.695G>A	p.Gly232Glu	missense_variant	6/17	1		ENSP00000259271.3
GAD2	ENST00000648567.1	c.353G>A	p.Gly118Glu	missense_variant	6/17			ENSP00000498009.1
GAD2	ENST00000376248.1	n.542G>A		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.00590 AC: 898 AN: 152148 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00961

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00875

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00646 AC: 1621 AN: 251122 Hom.: 11 AF XY: 0.00626 AC XY: 849 AN XY: 135728

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.0135

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.00994

Gnomad NFE exome AF: 0.00913

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00802 AC: 11719 AN: 1461122 Hom.: 69 Cov.: 29 AF XY: 0.00779 AC XY: 5663 AN XY: 726902

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.00927

Gnomad4 NFE exome AF: 0.00895

Gnomad4 OTH exome AF: 0.00818

GnomAD4 genome AF: 0.00590 AC: 898 AN: 152266 Hom.: 2 Cov.: 32 AF XY: 0.00602 AC XY: 448 AN XY: 74444

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00961

Gnomad4 NFE AF: 0.00875

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00821 Hom.: 13

Bravo AF: 0.00557

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0102 AC: 88

ExAC AF: 0.00674 AC: 818

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00769

EpiControl AF: 0.00688

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	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.79
DEOGEN2	Benign	0.24	T;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	.;D;D
MetaRNN	Benign	0.0072	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N;N;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.29	N;N;.
REVEL	Benign	0.073
Sift	Benign	0.47	T;T;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.046	B;B;.
Vest4		0.28
MVP		0.10
MPC		0.52
ClinPred		0.025	T
GERP RS		5.2
Varity_R		0.32
gMVP		0.88

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: rs2839673; hg19: chr10-26513551;