rs2839673

Variant names:

• chr10-26224622-G-A
• rs2839673
• NM_001134366.2:c.695G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-26224622-G-A
• chr10-26224622-G-C

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 774469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 898 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134366.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD2	NM_001134366.2	MANE Select	c.695G>A	p.Gly232Glu	missense	Exon 6 of 16	NP_001127838.1
	GAD2	NM_000818.3		c.695G>A	p.Gly232Glu	missense	Exon 6 of 17	NP_000809.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD2	ENST00000376261.8	TSL:1 MANE Select	c.695G>A	p.Gly232Glu	missense	Exon 6 of 16	ENSP00000365437.3
	GAD2	ENST00000259271.7	TSL:1	c.695G>A	p.Gly232Glu	missense	Exon 6 of 17	ENSP00000259271.3
	GAD2	ENST00000648567.1		c.353G>A	p.Gly118Glu	missense	Exon 6 of 17	ENSP00000498009.1

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

GnomAD2 exomes AF: 0.00646 AC: 1621 AN: 251122 AF XY: 0.00626

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 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

African (AFR) AF: 0.00146 AC: 49 AN: 33476

American (AMR) AF: 0.00291 AC: 130 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 369 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00252 AC: 217 AN: 86208

European-Finnish (FIN) AF: 0.00927 AC: 495 AN: 53416

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.00895 AC: 9951 AN: 1111400

Other (OTH) AF: 0.00818 AC: 494 AN: 60366

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

African (AFR) AF: 0.00156 AC: 65 AN: 41548

American (AMR) AF: 0.00425 AC: 65 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.00961 AC: 102 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00875 AC: 595 AN: 68024

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00781 Hom.: 19

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

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
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
Eigen	Benign	-0.16
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N
PhyloP100		6.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.073
Sift	Benign	0.47	T
Sift4G	Benign	1.0	T
Polyphen		0.046	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
Mutation Taster		=78/22	polymorphism

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: rs2839673; hg19: chr10-26513551;