2-170815885-C-G

Variant names:

• chr2-170815885-C-G
• rs3762555
• ENST00000663207.2:n.939G>C

Variant summary

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

The ENST00000663207.2(ERICH2-DT):​n.939G>C 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 0.698 in 152,174 control chromosomes in the GnomAD database, including 37,859 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 0.70 (37859 hom., cov: 34)
• Consequence: ERICH2-DT ENST00000663207.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.501
• Publications: 6 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=-0.73).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1-AS1	NR_197761.1	n.1244G>C		non_coding_transcript_exon_variant	Exon 4 of 4
GAD1-AS1	NR_197762.1	n.1013G>C		non_coding_transcript_exon_variant	Exon 3 of 3
GAD1-AS1	NR_197763.1	n.1070G>C		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.939G>C		non_coding_transcript_exon_variant	Exon 2 of 2
GAD1	ENST00000454603.5	c.-64+2463C>G		intron_variant	Intron 1 of 3	4		ENSP00000402366.1
ERICH2-DT	ENST00000728834.1	n.358+969G>C		intron_variant	Intron 1 of 4

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106178 AN: 152056 Hom.: 37827 Cov.: 34

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.744

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.768

Gnomad OTH AF: 0.729

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

GnomAD4 genome AF: 0.698 AC: 106264 AN: 152174 Hom.: 37859 Cov.: 34 AF XY: 0.699 AC XY: 51972 AN XY: 74394

African (AFR) AF: 0.540 AC: 22426 AN: 41524

American (AMR) AF: 0.756 AC: 11571 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 2425 AN: 3472

East Asian (EAS) AF: 0.712 AC: 3666 AN: 5148

South Asian (SAS) AF: 0.752 AC: 3627 AN: 4822

European-Finnish (FIN) AF: 0.744 AC: 7884 AN: 10598

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.768 AC: 52235 AN: 67990

Other (OTH) AF: 0.729 AC: 1541 AN: 2114

Alfa AF: 0.645 Hom.: 1998

Bravo AF: 0.692

Asia WGS AF: 0.750 AC: 2605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.3
DANN	Benign	0.68
PhyloP100		-0.50
PromoterAI		0.021	Neutral

Splicing

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

Other links and lift over

dbSNP: rs3762555; hg19: chr2-171672395;