2-170818671-C-A

Position:

chr2-170818671-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP2PP3BP6_Very_StrongBS1BS2

The NM_000817.3(GAD1):c.80C>A(p.Thr27Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000272 in 1,614,022 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00027 ( 3 hom. )

Consequence

GAD1
NM_000817.3 missense, splice_region

Scores

Splicing: ADA: 0.9675

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: 5.21

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GAD1. . Gene score misZ 2.3151 (greater than the threshold 3.09). Trascript score misZ 3.7409 (greater than threshold 3.09). GenCC has associacion of gene with cerebral palsy, spastic quadriplegic, 1, developmental and epileptic encephalopathy 89, early infantile epileptic encephalopathy, spastic quadriplegic cerebral palsy, neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 2-170818671-C-A is Benign according to our data. Variant chr2-170818671-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 560641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000289 (44/152324) while in subpopulation EAS AF= 0.00791 (41/5186). AF 95% confidence interval is 0.00599. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAD1	NM_000817.3 linkuse as main transcript	c.80C>A	p.Thr27Lys	missense_variant, splice_region_variant	2/17	ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8 linkuse as main transcript	c.80C>A	p.Thr27Lys	missense_variant, splice_region_variant	2/17	1	NM_000817.3	ENSP00000350928	P1	Q99259-1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00789

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000765

AC:

192

AN:

251036

Hom.:

AF XY:

0.000707

AC XY:

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00854

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000270

AC:

395

AN:

1461698

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

173

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00801

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000289

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00791

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000452

Hom.:

Bravo

AF:

0.000400

ExAC

AF:

0.000749

AC:

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

Benign:2

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2023	- -

Infantile spasms

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Aug 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

0.00028

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

.;.;.;T;.;.;.;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

D;D;D;D;D;.;D;D

M_CAP

Benign

0.070

MetaRNN

Benign

0.010

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.41

.;.;N;N;N;N;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.8

D;D;.;N;N;N;N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.016

D;D;.;T;T;T;D;T

Sift4G

Benign

0.36

T;D;T;T;T;T;T;T

Polyphen

0.085, 0.73

.;.;.;B;P;P;.;.

Vest4

0.75, 0.69, 0.82, 0.82

MVP

0.93

MPC

0.81

ClinPred

0.088

GERP RS

5.7

Varity_R

0.26

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.78

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