2-170818553-A-C

Position:

• chr2-170818553-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000817.3(GAD1):​c.-39A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000938 in 1,582,168 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00077 (5 hom.)
• Consequence: GAD1 NM_000817.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.40

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-170818553-A-C is Benign according to our data. Variant chr2-170818553-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 893995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00252 (383/152242) while in subpopulation AMR AF= 0.00549 (84/15290). AF 95% confidence interval is 0.00455. There are 2 homozygotes in gnomad4. There are 189 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD1	NM_000817.3	c.-39A>C		5_prime_UTR_variant	2/17	ENST00000358196.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD1	ENST00000358196.8	c.-39A>C		5_prime_UTR_variant	2/17	1	NM_000817.3	P1

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 384 AN: 152124 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00128 AC: 321 AN: 251020 Hom.: 1 AF XY: 0.00127 AC XY: 173 AN XY: 135758

Gnomad AFR exome AF: 0.00561

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00517

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.000706

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000770 AC: 1101 AN: 1429926 Hom.: 5 Cov.: 26 AF XY: 0.000782 AC XY: 558 AN XY: 713590

Gnomad4 AFR exome AF: 0.00672

Gnomad4 AMR exome AF: 0.00175

Gnomad4 ASJ exome AF: 0.00509

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00100

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.000366

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00252 AC: 383 AN: 152242 Hom.: 2 Cov.: 31 AF XY: 0.00254 AC XY: 189 AN XY: 74432

Gnomad4 AFR AF: 0.00496

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00217 Hom.: 0

Bravo AF: 0.00295

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	GAD1: BS1 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.72

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: rs45617531; hg19: chr2-171675063;