10-26217883-G-C

Variant names:

• chr10-26217883-G-C
• NM_001134366.2:c.178G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134366.2(GAD2):​c.178G>C​(p.Gly60Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GAD2 NM_001134366.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.57

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13856536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.178G>C	p.Gly60Arg	missense_variant	Exon 3 of 16	ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.178G>C	p.Gly60Arg	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.178G>C	p.Gly60Arg	missense_variant	Exon 3 of 16	1	NM_001134366.2	ENSP00000365437.3
GAD2	ENST00000259271.7	c.178G>C	p.Gly60Arg	missense_variant	Exon 3 of 17	1		ENSP00000259271.3
GAD2	ENST00000428517.2	n.178G>C		non_coding_transcript_exon_variant	Exon 3 of 4	1		ENSP00000390434.2
GAD2	ENST00000648567	c.-165G>C		5_prime_UTR_variant	Exon 3 of 17			ENSP00000498009.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455202 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723536

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	0.053
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.67	.;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.46	N;N
REVEL	Benign	0.13
Sift	Benign	0.10	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.0	B;B
Vest4		0.34
MutPred		0.16		Gain of methylation at G60 (P = 0.04);Gain of methylation at G60 (P = 0.04);
MVP		0.45
MPC		0.47
ClinPred		0.87	D
GERP RS		5.0
Varity_R		0.078
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-26506812;