chr2-170815865-C-T

Variant names:

• chr2-170815865-C-T
• rs6755102
• ENST00000663207.2:n.959G>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.959G>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 0.0211 in 152,302 control chromosomes in the GnomAD database, including 235 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 0.021 (235 hom., cov: 33)
• Consequence: ERICH2-DT ENST00000663207.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.975
• Publications: 2 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=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1-AS1	NR_197761.1	n.1264G>A		non_coding_transcript_exon_variant	Exon 4 of 4
GAD1-AS1	NR_197762.1	n.1033G>A		non_coding_transcript_exon_variant	Exon 3 of 3
GAD1-AS1	NR_197763.1	n.1090G>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.959G>A		non_coding_transcript_exon_variant	Exon 2 of 2
GAD1	ENST00000454603.5	c.-64+2443C>T		intron_variant	Intron 1 of 3	4		ENSP00000402366.1
ERICH2-DT	ENST00000728834.1	n.358+989G>A		intron_variant	Intron 1 of 4

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3202 AN: 152184 Hom.: 236 Cov.: 33

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.0430

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.0287

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

GnomAD4 genome AF: 0.0211 AC: 3211 AN: 152302 Hom.: 235 Cov.: 33 AF XY: 0.0229 AC XY: 1707 AN XY: 74462

African (AFR) AF: 0.0184 AC: 767 AN: 41572

American (AMR) AF: 0.0197 AC: 301 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.273 AC: 1406 AN: 5150

South Asian (SAS) AF: 0.0430 AC: 208 AN: 4832

European-Finnish (FIN) AF: 0.00509 AC: 54 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00550 AC: 374 AN: 68034

Other (OTH) AF: 0.0293 AC: 62 AN: 2116

Alfa AF: 0.00581 Hom.: 4

Bravo AF: 0.0230

Asia WGS AF: 0.126 AC: 437 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.4
DANN	Benign	0.82
PhyloP100		-0.97
PromoterAI		0.043	Neutral

Splicing

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

Other links and lift over

dbSNP: rs6755102; hg19: chr2-171672375;