NM_000817.3:c.752-252C>G

Variant names:

• chr2-170845254-C-G
• rs16858977
• NM_000817.3:c.752-252C>G

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.752-252C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 547,186 control chromosomes in the GnomAD database, including 28,562 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7489 hom., cov: 32)
  • Exomes 𝑓: 0.32 (21073 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.77
• Publications: 2 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: 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-170845254-C-G is Benign according to our data. Variant chr2-170845254-C-G is described in ClinVar as Benign. ClinVar VariationId is 1277575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	NM_000817.3	MANE Select	c.752-252C>G		intron	N/A	NP_000808.2	Q99259-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000358196.8	TSL:1 MANE Select	c.752-252C>G		intron	N/A	ENSP00000350928.3	Q99259-1
	GAD1	ENST00000493875.5	TSL:1	n.752-252C>G		intron	N/A	ENSP00000434696.1	Q99259-4
	GAD1	ENST00000883273.1		c.752-252C>G		intron	N/A	ENSP00000553332.1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47051 AN: 151902 Hom.: 7468 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.303

GnomAD4 exome AF: 0.317 AC: 125413 AN: 395166 Hom.: 21073 AF XY: 0.323 AC XY: 67795 AN XY: 210094

African (AFR) AF: 0.310 AC: 3522 AN: 11376

American (AMR) AF: 0.328 AC: 6023 AN: 18364

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 2802 AN: 12186

East Asian (EAS) AF: 0.482 AC: 12179 AN: 25262

South Asian (SAS) AF: 0.408 AC: 18543 AN: 45456

European-Finnish (FIN) AF: 0.327 AC: 7425 AN: 22684

Middle Eastern (MID) AF: 0.262 AC: 446 AN: 1702

European-Non Finnish (NFE) AF: 0.287 AC: 67611 AN: 235448

Other (OTH) AF: 0.302 AC: 6862 AN: 22688

GnomAD4 genome AF: 0.310 AC: 47127 AN: 152020 Hom.: 7489 Cov.: 32 AF XY: 0.314 AC XY: 23355 AN XY: 74290

African (AFR) AF: 0.304 AC: 12610 AN: 41468

American (AMR) AF: 0.320 AC: 4890 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 834 AN: 3466

East Asian (EAS) AF: 0.533 AC: 2748 AN: 5152

South Asian (SAS) AF: 0.425 AC: 2045 AN: 4816

European-Finnish (FIN) AF: 0.329 AC: 3473 AN: 10562

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

European-Non Finnish (NFE) AF: 0.289 AC: 19629 AN: 67960

Other (OTH) AF: 0.306 AC: 647 AN: 2112

Alfa AF: 0.164 Hom.: 323

Bravo AF: 0.308

Asia WGS AF: 0.460 AC: 1597 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	11
DANN	Benign	0.55
PhyloP100		1.8
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: rs16858977; hg19: chr2-171701764;