rs45566933

chr2-170844088-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM2 PP2 BP4_Moderate BP6 BS1

The NM_000817.3(GAD1):c.682A>C(p.Ile228Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000516 in 1,611,270 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: GAD1 NM_000817.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 5.41

Genes affected

GAD1 (HGNC:4092): (glutamate decarboxylase 1) 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 autoantigen and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Deficiency in this enzyme has been shown to lead to pyridoxine dependency with seizures. Alternative splicing of this gene results in two products, the predominant 67-kD form and a less-frequent 25-kD form. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GAD1
• BP4: Computational evidence support a benign effect (MetaRNN=0.079863876).
• BP6: Variant 2-170844088-A-C is Benign according to our data. Variant chr2-170844088-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 332231.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000387 (59/152352) while in subpopulation NFE AF= 0.000661 (45/68036). AF 95% confidence interval is 0.000507. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD1	NM_000817.3	c.682A>C	p.Ile228Leu	missense_variant	7/17	ENST00000358196.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD1	ENST00000358196.8	c.682A>C	p.Ile228Leu	missense_variant	7/17	1	NM_000817.3	P1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000661

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000322 AC: 81 AN: 251304 Hom.: 1 AF XY: 0.000302 AC XY: 41 AN XY: 135830

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000529 AC: 772 AN: 1458918 Hom.: 1 Cov.: 28 AF XY: 0.000486 AC XY: 353 AN XY: 726096

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000647

Gnomad4 OTH exome AF: 0.000581

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74496

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000661

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000545 Hom.: 0

Bravo AF: 0.000476

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	GAD1: BS1 -

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2022

The c.682A>C (p.I228L) alteration is located in exon 7 (coding exon 6) of the GAD1 gene. This alteration results from a A to C substitution at nucleotide position 682, causing the isoleucine (I) at amino acid position 228 to be replaced by a leucine (L). 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	0.075
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Benign	0.96
Eigen	Benign	0.084
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
Sift4G	Benign	0.62	T;T
Polyphen		0.0020	.;B
Vest4		0.26
MutPred		0.23		Loss of MoRF binding (P = 0.1715);Loss of MoRF binding (P = 0.1715);
MVP		0.29
MPC		0.59
ClinPred		0.040	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.69

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: rs45566933; hg19: chr2-171700598;