Genetic Variant NM_000817.3:c.80C>A (chr2-170818671-C-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_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

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

early infantile epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy 89
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
spastic quadriplegic cerebral palsy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
cerebral palsy, spastic quadriplegic, 1
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GAD1 links:

GAD1-AS1 (HGNC:40250):

GAD1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Splicing predictors support a deleterious 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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000817.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAD1	NM_000817.3	MANE Select	c.80C>A	p.Thr27Lys	missense splice_region	Exon 2 of 17	NP_000808.2	Q99259-1
GAD1	NM_013445.4		c.80C>A	p.Thr27Lys	missense splice_region	Exon 2 of 7	NP_038473.2
GAD1-AS1	NR_197761.1		n.-20G>T		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAD1	ENST00000358196.8	TSL:1 MANE Select	c.80C>A	p.Thr27Lys	missense splice_region	Exon 2 of 17	ENSP00000350928.3	Q99259-1
GAD1	ENST00000375272.5	TSL:1	c.80C>A	p.Thr27Lys	missense splice_region	Exon 2 of 7	ENSP00000364421.1	Q99259-3
GAD1	ENST00000493875.5	TSL:1	n.80C>A		splice_region non_coding_transcript_exon	Exon 1 of 17	ENSP00000434696.1	Q99259-4

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

GnomAD2 exomes

AF:

0.000765

AC:

192

AN:

251036

AF XY:

0.000707

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 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

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.000581

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00801

AC:

318

AN:

39700

South Asian (SAS)

AF:

0.000197

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111838

Other (OTH)

AF:

0.000364

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000289

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41578

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00791

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000383

Hom.:

Bravo

AF:

0.000400

ExAC

AF:

0.000749

AC:

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (2)

Infantile spasms (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

0.00028

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.070

MetaRNN

Benign

0.010

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.41

PhyloP100

5.2

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.32

Sift

Uncertain

0.016

Sift4G

Benign

0.36

Polyphen

0.085

Vest4

0.75

MVP

0.93

MPC

0.81

ClinPred

0.088

GERP RS

5.7

Varity_R

0.26

gMVP

0.45

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over