10-26217983-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001134366.2(GAD2):c.278A>C(p.His93Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAD2 NM_001134366.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD2	NM_001134366.2	c.278A>C	p.His93Pro	missense_variant	3/16	ENST00000376261.8
GAD2	NM_000818.3	c.278A>C	p.His93Pro	missense_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD2	ENST00000376261.8	c.278A>C	p.His93Pro	missense_variant	3/16	1	NM_001134366.2	P1
GAD2	ENST00000259271.7	c.278A>C	p.His93Pro	missense_variant	3/17	1		P1
GAD2	ENST00000428517.2	c.278A>C	p.His93Pro	missense_variant	3/4	1
GAD2	ENST00000648567.1	c.-65A>C		5_prime_UTR_variant	3/17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243450 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132576

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457574 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

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 15, 2023

The c.278A>C (p.H93P) alteration is located in exon 3 (coding exon 3) of the GAD2 gene. This alteration results from a A to C substitution at nucleotide position 278, causing the histidine (H) at amino acid position 93 to be replaced by a proline (P). 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	0.31
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	21
Dann	Benign	0.66
DEOGEN2	Benign	0.40	T;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.14	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0	B;B
Vest4		0.68
MutPred		0.55		Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);
MVP		0.58
MPC		0.63
ClinPred		0.27	T
GERP RS		5.8
Varity_R		0.77
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1357321101; hg19: chr10-26506912;