rs1978340

Variant names:

• chr2-170813611-G-A
• rs1978340
• ENST00000662804.1:n.60C>T

Variant summary

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

The ENST00000662804.1(ERICH2-DT):​n.60C>T 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 0.253 in 152,142 control chromosomes in the GnomAD database, including 5,311 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 0.25 (5311 hom., cov: 32)
• Consequence: ERICH2-DT ENST00000662804.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.399
• Publications: 16 publications found

Genes affected

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

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=-0.52).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1	XM_011510922.1	c.-64+189G>A		intron_variant	Intron 1 of 16		XP_011509224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERICH2-DT	ENST00000662804.1	n.60C>T		non_coding_transcript_exon_variant	Exon 1 of 4
GAD1	ENST00000454603.5	c.-64+189G>A		intron_variant	Intron 1 of 3	4		ENSP00000402366.1
ERICH2-DT	ENST00000728834.1	n.358+3243C>T		intron_variant	Intron 1 of 4

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38425 AN: 152024 Hom.: 5301 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.267

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

GnomAD4 genome AF: 0.253 AC: 38450 AN: 152142 Hom.: 5311 Cov.: 32 AF XY: 0.254 AC XY: 18894 AN XY: 74372

African (AFR) AF: 0.147 AC: 6094 AN: 41530

American (AMR) AF: 0.234 AC: 3583 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 896 AN: 3470

East Asian (EAS) AF: 0.227 AC: 1175 AN: 5178

South Asian (SAS) AF: 0.354 AC: 1705 AN: 4822

European-Finnish (FIN) AF: 0.310 AC: 3270 AN: 10558

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20746 AN: 67968

Other (OTH) AF: 0.268 AC: 566 AN: 2114

Alfa AF: 0.265 Hom.: 1554

Bravo AF: 0.242

Asia WGS AF: 0.302 AC: 1048 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.0
DANN	Benign	0.93
PhyloP100		-0.40
PromoterAI		0.012	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1978340; hg19: chr2-171670121;