10-26217969-C-A

Variant names:

• chr10-26217969-C-A
• rs755051252
• NM_001134366.2:c.264C>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001134366.2(GAD2):​c.264C>A​(p.Asn88Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,458,786 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: GAD2 NM_001134366.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.264C>A	p.Asn88Lys	missense_variant	Exon 3 of 16	ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.264C>A	p.Asn88Lys	missense_variant	Exon 3 of 17		NP_000809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD2	ENST00000376261.8	c.264C>A	p.Asn88Lys	missense_variant	Exon 3 of 16	1	NM_001134366.2	ENSP00000365437.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000204 AC: 5 AN: 244918 Hom.: 0 AF XY: 0.0000225 AC XY: 3 AN XY: 133244

Gnomad AFR exome AF: 0.0000631

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1458786 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 725564

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.264C>A (p.N88K) alteration is located in exon 3 (coding exon 3) of the GAD2 gene. This alteration results from a C to A substitution at nucleotide position 264, causing the asparagine (N) at amino acid position 88 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	0.26
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	0.014
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.73	.;T
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.087
Sift	Benign	0.14	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.14	B;B
Vest4		0.59
MutPred		0.47		Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);
MVP		0.49
MPC		0.45
ClinPred		0.19	T
GERP RS		3.7
Varity_R		0.40
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs755051252; hg19: chr10-26506898;