rs3791878

Variant names:

• chr2-170815681-G-T
• rs3791878
• ENST00000663207.2:n.1143C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000663207.2(ERICH2-DT):​n.1143C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,114 control chromosomes in the GnomAD database, including 5,083 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (5083 hom., cov: 32)
• Consequence: ERICH2-DT ENST00000663207.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.405
• Publications: 30 publications found

Genes affected

ERICH2-DT (HGNC:55686): (ERICH2 divergent transcript)

GAD1-AS1 (HGNC:40250):

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1-AS1	NR_197761.1	n.1448C>A		non_coding_transcript_exon_variant	Exon 4 of 4
GAD1-AS1	NR_197762.1	n.1217C>A		non_coding_transcript_exon_variant	Exon 3 of 3
GAD1-AS1	NR_197763.1	n.1274C>A		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERICH2-DT	ENST00000663207.2	n.1143C>A		non_coding_transcript_exon_variant	Exon 2 of 2
GAD1	ENST00000454603.5	c.-64+2259G>T		intron_variant	Intron 1 of 3	4		ENSP00000402366.1
ERICH2-DT	ENST00000728834.1	n.358+1173C>A		intron_variant	Intron 1 of 4

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35418 AN: 151996 Hom.: 5080 Cov.: 32

Gnomad AFR AF: 0.0646

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.244

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.233 AC: 35423 AN: 152114 Hom.: 5083 Cov.: 32 AF XY: 0.234 AC XY: 17381 AN XY: 74348

African (AFR) AF: 0.0644 AC: 2676 AN: 41550

American (AMR) AF: 0.222 AC: 3388 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 964 AN: 3466

East Asian (EAS) AF: 0.228 AC: 1180 AN: 5168

South Asian (SAS) AF: 0.332 AC: 1599 AN: 4820

European-Finnish (FIN) AF: 0.326 AC: 3449 AN: 10586

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21300 AN: 67952

Other (OTH) AF: 0.245 AC: 516 AN: 2108

Alfa AF: 0.299 Hom.: 11025

Bravo AF: 0.218

Asia WGS AF: 0.280 AC: 972 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.4
DANN	Benign	0.65
PhyloP100		-0.41
PromoterAI		-0.00080	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3791878; hg19: chr2-171672191;