2-170821869-C-T

Variant names:

• chr2-170821869-C-T
• rs2241165
• NM_000817.3:c.83-218C>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.83-218C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 570,728 control chromosomes in the GnomAD database, including 147,476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (33071 hom., cov: 34)
  • Exomes 𝑓: 0.73 (114405 hom.)
• Consequence: GAD1 NM_000817.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.38
• Publications: 27 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=-0.86).
• BP6: Variant 2-170821869-C-T is Benign according to our data. Variant chr2-170821869-C-T is described in ClinVar as Benign. ClinVar VariationId is 1233820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.752 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	NM_000817.3	MANE Select	c.83-218C>T		intron	N/A	NP_000808.2
	GAD1	NM_013445.4		c.83-218C>T		intron	N/A	NP_038473.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000358196.8	TSL:1 MANE Select	c.83-218C>T		intron	N/A	ENSP00000350928.3
	GAD1	ENST00000375272.5	TSL:1	c.83-218C>T		intron	N/A	ENSP00000364421.1
	GAD1	ENST00000493875.5	TSL:1	n.83-218C>T		intron	N/A	ENSP00000434696.1

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96434 AN: 152128 Hom.: 33058 Cov.: 34

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.743

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.670

GnomAD4 exome AF: 0.735 AC: 307415 AN: 418482 Hom.: 114405 Cov.: 3 AF XY: 0.738 AC XY: 163158 AN XY: 221224

African (AFR) AF: 0.338 AC: 3916 AN: 11570

American (AMR) AF: 0.721 AC: 13202 AN: 18310

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 8426 AN: 12622

East Asian (EAS) AF: 0.700 AC: 19978 AN: 28550

South Asian (SAS) AF: 0.764 AC: 33807 AN: 44248

European-Finnish (FIN) AF: 0.745 AC: 19839 AN: 26636

Middle Eastern (MID) AF: 0.711 AC: 2164 AN: 3042

European-Non Finnish (NFE) AF: 0.758 AC: 189084 AN: 249510

Other (OTH) AF: 0.708 AC: 16999 AN: 23994

GnomAD4 genome AF: 0.634 AC: 96472 AN: 152246 Hom.: 33071 Cov.: 34 AF XY: 0.638 AC XY: 47467 AN XY: 74430

African (AFR) AF: 0.338 AC: 14049 AN: 41540

American (AMR) AF: 0.725 AC: 11085 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2336 AN: 3470

East Asian (EAS) AF: 0.714 AC: 3680 AN: 5156

South Asian (SAS) AF: 0.766 AC: 3698 AN: 4826

European-Finnish (FIN) AF: 0.743 AC: 7884 AN: 10616

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.757 AC: 51522 AN: 68016

Other (OTH) AF: 0.670 AC: 1418 AN: 2116

Alfa AF: 0.720 Hom.: 168033

Bravo AF: 0.617

Asia WGS AF: 0.736 AC: 2556 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.17
DANN	Benign	0.75
PhyloP100		-2.4
PromoterAI		-0.013	Neutral
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: rs2241165; hg19: chr2-171678379; COSMIC: COSV60154465; COSMIC: COSV60154465;