rs701492

Variant names:

• chr2-170845970-C-T
• rs701492
• NM_000817.3:c.948-39C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000817.3(GAD1):​c.948-39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 1,578,180 control chromosomes in the GnomAD database, including 67,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6075 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61605 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.782
• Publications: 19 publications found

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: G2P, Labcorp Genetics (formerly Invitae)
• 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-170845970-C-T is Benign according to our data. Variant chr2-170845970-C-T is described in ClinVar as [Benign]. Clinvar id is 1260220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	NM_000817.3	c.948-39C>T		intron_variant	Intron 9 of 16	ENST00000358196.8	NP_000808.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD1	ENST00000358196.8	c.948-39C>T		intron_variant	Intron 9 of 16	1	NM_000817.3	ENSP00000350928.3
GAD1	ENST00000493875.5	n.948-39C>T		intron_variant	Intron 8 of 16	1		ENSP00000434696.1
GAD1	ENST00000625689.2	c.948-39C>T		intron_variant	Intron 9 of 17	5		ENSP00000486612.1
GAD1	ENST00000414527.6	n.*133-39C>T		intron_variant	Intron 8 of 15	5		ENSP00000403849.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42706 AN: 151876 Hom.: 6059 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.268

GnomAD2 exomes AF: 0.297 AC: 74389 AN: 250060 AF XY: 0.300

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.284

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.291 AC: 414352 AN: 1426186 Hom.: 61605 Cov.: 25 AF XY: 0.292 AC XY: 207817 AN XY: 711794

African (AFR) AF: 0.258 AC: 8460 AN: 32732

American (AMR) AF: 0.324 AC: 14469 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5642 AN: 25902

East Asian (EAS) AF: 0.287 AC: 11330 AN: 39502

South Asian (SAS) AF: 0.381 AC: 32561 AN: 85550

European-Finnish (FIN) AF: 0.319 AC: 17028 AN: 53394

Middle Eastern (MID) AF: 0.245 AC: 1364 AN: 5574

European-Non Finnish (NFE) AF: 0.284 AC: 307010 AN: 1079780

Other (OTH) AF: 0.279 AC: 16488 AN: 59126

GnomAD4 genome AF: 0.281 AC: 42774 AN: 151994 Hom.: 6075 Cov.: 32 AF XY: 0.284 AC XY: 21115 AN XY: 74266

African (AFR) AF: 0.258 AC: 10702 AN: 41470

American (AMR) AF: 0.293 AC: 4485 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 785 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1522 AN: 5166

South Asian (SAS) AF: 0.384 AC: 1850 AN: 4812

European-Finnish (FIN) AF: 0.323 AC: 3397 AN: 10510

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19220 AN: 67964

Other (OTH) AF: 0.271 AC: 572 AN: 2114

Alfa AF: 0.280 Hom.: 25540

Bravo AF: 0.277

Asia WGS AF: 0.343 AC: 1191 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	15
DANN	Benign	0.49
PhyloP100		0.78
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs701492; hg19: chr2-171702480; COSMIC: COSV60151788; COSMIC: COSV60151788;