10-26217862-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001134366.2(GAD2):c.157G>A(p.Glu53Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GAD2 NM_001134366.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD2	NM_001134366.2	c.157G>A	p.Glu53Lys	missense_variant	3/16	ENST00000376261.8
GAD2	NM_000818.3	c.157G>A	p.Glu53Lys	missense_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD2	ENST00000376261.8	c.157G>A	p.Glu53Lys	missense_variant	3/16	1	NM_001134366.2	P1
GAD2	ENST00000259271.7	c.157G>A	p.Glu53Lys	missense_variant	3/17	1		P1
GAD2	ENST00000428517.2	c.157G>A	p.Glu53Lys	missense_variant	3/4	1
GAD2	ENST00000648567.1	c.-186G>A		5_prime_UTR_variant	3/17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454656 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.157G>A (p.E53K) alteration is located in exon 3 (coding exon 3) of the GAD2 gene. This alteration results from a G to A substitution at nucleotide position 157, causing the glutamic acid (E) at amino acid position 53 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.098	T;T
Polyphen		0.62	P;P
Vest4		0.57
MutPred		0.34		Gain of ubiquitination at E53 (P = 0.0039);Gain of ubiquitination at E53 (P = 0.0039);
MVP		0.69
MPC		0.46
ClinPred		0.85	D
GERP RS		5.9
Varity_R		0.22
gMVP		0.46

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: rs1844397943; hg19: chr10-26506791; COSMIC: COSV99393115; COSMIC: COSV99393115;