10-26219060-G-A

Variant names:

• chr10-26219060-G-A
• rs139888003
• NM_001134366.2:c.304G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001134366.2(GAD2):​c.304G>A​(p.Asp102Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,584,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: GAD2 NM_001134366.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08266285).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.304G>A	p.Asp102Asn	missense_variant	Exon 4 of 16	ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.304G>A	p.Asp102Asn	missense_variant	Exon 4 of 17		NP_000809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD2	ENST00000376261.8	c.304G>A	p.Asp102Asn	missense_variant	Exon 4 of 16	1	NM_001134366.2	ENSP00000365437.3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000637 AC: 15 AN: 235634 AF XY: 0.0000864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000161 AC: 230 AN: 1432590 Hom.: 0 Cov.: 31 AF XY: 0.000154 AC XY: 109 AN XY: 709362

African (AFR) AF: 0.00 AC: 0 AN: 32592

American (AMR) AF: 0.00 AC: 0 AN: 39798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25354

East Asian (EAS) AF: 0.00 AC: 0 AN: 38946

South Asian (SAS) AF: 0.00 AC: 0 AN: 81124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.000209 AC: 229 AN: 1096770

Other (OTH) AF: 0.0000169 AC: 1 AN: 59216

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.304G>A (p.D102N) alteration is located in exon 4 (coding exon 4) of the GAD2 gene. This alteration results from a G to A substitution at nucleotide position 304, causing the aspartic acid (D) at amino acid position 102 to be replaced by an asparagine (N). 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	0.064
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.42
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.74	.;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.083	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.29	N;N
PhyloP100		1.7
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.76	N;N
REVEL	Benign	0.16
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.080
MVP		0.49
MPC		0.38
ClinPred		0.026	T
GERP RS		3.6
Varity_R		0.12
gMVP		0.33
Mutation Taster		=90/10	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: rs139888003; hg19: chr10-26507989;