2-170815568-C-G

Variant names:

• chr2-170815568-C-G
• rs3762556
• ENST00000663207.2:n.1256G>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.1256G>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 0.285 in 152,002 control chromosomes in the GnomAD database, including 6,993 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 0.28 (6993 hom., cov: 31)
• Consequence: ERICH2-DT ENST00000663207.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.409
• Publications: 7 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=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1-AS1	NR_197761.1	n.1561G>C		non_coding_transcript_exon_variant	Exon 4 of 4
GAD1-AS1	NR_197762.1	n.1330G>C		non_coding_transcript_exon_variant	Exon 3 of 3
GAD1-AS1	NR_197763.1	n.1387G>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.1256G>C		non_coding_transcript_exon_variant	Exon 2 of 2
ERICH2-DT	ENST00000729370.1	n.395G>C		non_coding_transcript_exon_variant	Exon 2 of 2
GAD1	ENST00000454603.5	c.-64+2146C>G		intron_variant	Intron 1 of 3	4		ENSP00000402366.1

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43205 AN: 151884 Hom.: 6985 Cov.: 31

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.304

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

GnomAD4 genome AF: 0.285 AC: 43245 AN: 152002 Hom.: 6993 Cov.: 31 AF XY: 0.288 AC XY: 21413 AN XY: 74298

African (AFR) AF: 0.120 AC: 4988 AN: 41472

American (AMR) AF: 0.352 AC: 5376 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1018 AN: 3466

East Asian (EAS) AF: 0.503 AC: 2588 AN: 5150

South Asian (SAS) AF: 0.391 AC: 1882 AN: 4818

European-Finnish (FIN) AF: 0.337 AC: 3555 AN: 10556

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

European-Non Finnish (NFE) AF: 0.336 AC: 22832 AN: 67960

Other (OTH) AF: 0.304 AC: 643 AN: 2112

Alfa AF: 0.174 Hom.: 390

Bravo AF: 0.279

Asia WGS AF: 0.429 AC: 1486 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.75
DANN	Benign	0.60
PhyloP100		-0.41

Splicing

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

Other links and lift over

dbSNP: rs3762556; hg19: chr2-171672078;