10-26219214-C-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_001134366.2(GAD2):c.458C>A(p.Pro153Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00659 in 1,613,700 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (39 hom.)
• Consequence: GAD2 NM_001134366.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.57

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 -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.009708941).
• BP6: Variant 10-26219214-C-A is Benign according to our data. Variant chr10-26219214-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 782118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 793 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD2	NM_001134366.2	c.458C>A	p.Pro153Gln	missense_variant	4/16	ENST00000376261.8
GAD2	NM_000818.3	c.458C>A	p.Pro153Gln	missense_variant	4/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD2	ENST00000376261.8	c.458C>A	p.Pro153Gln	missense_variant	4/16	1	NM_001134366.2	P1

Frequencies

GnomAD3 genomes AF: 0.00521 AC: 793 AN: 152150 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00801

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00551 AC: 1384 AN: 251140 Hom.: 6 AF XY: 0.00559 AC XY: 759 AN XY: 135740

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00321

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.00835

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00673 AC: 9840 AN: 1461432 Hom.: 39 Cov.: 31 AF XY: 0.00667 AC XY: 4851 AN XY: 727004

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00326

Gnomad4 FIN exome AF: 0.00983

Gnomad4 NFE exome AF: 0.00763

Gnomad4 OTH exome AF: 0.00586

GnomAD4 genome AF: 0.00521 AC: 793 AN: 152268 Hom.: 2 Cov.: 33 AF XY: 0.00510 AC XY: 380 AN XY: 74448

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.00801

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00755 Hom.: 8

Bravo AF: 0.00449

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00607 AC: 737

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	GAD2: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Benign	-0.28	T
MutationAssessor	Pathogenic	3.0	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.6	D;D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.014	D;D;.
Sift4G	Uncertain	0.019	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.80
MVP		0.59
MPC		1.2
ClinPred		0.017	T
GERP RS		5.6
Varity_R		0.78
gMVP		0.89

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: rs2839672; hg19: chr10-26508143;