2-170814656-C-T

Variant names:

• chr2-170814656-C-T
• rs872123
• ENST00000663207.2:n.2168G>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.2168G>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 0.641 in 152,094 control chromosomes in the GnomAD database, including 33,688 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 0.64 (33688 hom., cov: 32)
• Consequence: ERICH2-DT ENST00000663207.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38
• Publications: 8 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD1-AS1	NR_197761.1	n.2473G>A		non_coding_transcript_exon_variant	Exon 4 of 4
GAD1-AS1	NR_197762.1	n.2242G>A		non_coding_transcript_exon_variant	Exon 3 of 3
GAD1-AS1	NR_197763.1	n.2299G>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.2168G>A		non_coding_transcript_exon_variant	Exon 2 of 2
ERICH2-DT	ENST00000729370.1	n.1307G>A		non_coding_transcript_exon_variant	Exon 2 of 2
GAD1	ENST00000454603.5	c.-64+1234C>T		intron_variant	Intron 1 of 3	4		ENSP00000402366.1

Frequencies

GnomAD3 genomes AF: 0.641 AC: 97409 AN: 151976 Hom.: 33672 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.780

Gnomad AMR AF: 0.729

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.742

Gnomad FIN AF: 0.743

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.766

Gnomad OTH AF: 0.681

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

GnomAD4 genome AF: 0.641 AC: 97455 AN: 152094 Hom.: 33688 Cov.: 32 AF XY: 0.644 AC XY: 47876 AN XY: 74376

African (AFR) AF: 0.346 AC: 14324 AN: 41450

American (AMR) AF: 0.729 AC: 11146 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 2418 AN: 3466

East Asian (EAS) AF: 0.718 AC: 3718 AN: 5178

South Asian (SAS) AF: 0.744 AC: 3586 AN: 4820

European-Finnish (FIN) AF: 0.743 AC: 7861 AN: 10586

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.766 AC: 52076 AN: 67990

Other (OTH) AF: 0.681 AC: 1438 AN: 2112

Alfa AF: 0.604 Hom.: 2200

Bravo AF: 0.626

Asia WGS AF: 0.735 AC: 2552 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.25
DANN	Benign	0.66
PhyloP100		-1.4

Splicing

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

Other links and lift over

dbSNP: rs872123; hg19: chr2-171671166;