chr2-170816868-G-A

Position:

chr2-170816868-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000375272.5(GAD1):c.-248G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 158,256 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

GAD1
ENST00000375272.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.973

Variant links:

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]

GAD1 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 2-170816868-G-A is Benign according to our data. Variant chr2-170816868-G-A is described in ClinVar as [Benign]. Clinvar id is 332215.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00348 (528/151720) while in subpopulation AFR AF= 0.0119 (492/41390). AF 95% confidence interval is 0.011. There are 5 homozygotes in gnomad4. There are 251 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
GAD1	XM_011510922.1 linkuse as main transcript	c.-63-1661G>A	intron_variant
GAD1	NM_000817.3 linkuse as main transcript		upstream_gene_variant	ENST00000358196.8
GAD1	NM_013445.4 linkuse as main transcript		upstream_gene_variant
GAD1	XM_017003758.3 linkuse as main transcript		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000663207.1 linkuse as main transcript	n.324C>T		non_coding_transcript_exon_variant	1/2
GAD1	ENST00000358196.8 linkuse as main transcript			upstream_gene_variant		1	NM_000817.3	P1	Q99259-1

Frequencies

GnomAD3 genomes

AF:

0.00344

AC:

522

AN:

151602

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00240

GnomAD4 exome

AF:

0.000306

AC:

AN:

6536

Hom.:

Cov.:

AF XY:

0.000569

AC XY:

AN XY:

3514

show subpopulations

Gnomad4 AFR exome

AF:

0.0130

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00348

AC:

528

AN:

151720

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

251

AN XY:

74200

show subpopulations

Gnomad4 AFR

AF:

0.0119

Gnomad4 AMR

AF:

0.00190

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00238

Alfa

AF:

0.00291

Hom.:

Bravo

AF:

0.00388

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over