dbSNP rs3749035: ERICH2-DT:n.554T>G (chr2-170816270-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000663207.2(ERICH2-DT):n.554T>G 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 0.356 in 152,244 control chromosomes in the GnomAD database, including 10,211 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 0.36 ( 10191 hom., cov: 33)

Exomes 𝑓: 0.41 ( 20 hom. )

Consequence

ERICH2-DT
ENST00000663207.2 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.651

Publications

3 publications found

Variant links:

Genes affected

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

ERICH2-DT links:

GAD1-AS1 (HGNC:40250):

GAD1-AS1 links:

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)

GAD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
GAD1-AS1	NR_197761.1 link	n.859T>G	non_coding_transcript_exon_variant	Exon 4 of 4
GAD1-AS1	NR_197762.1 link	n.628T>G	non_coding_transcript_exon_variant	Exon 3 of 3
GAD1-AS1	NR_197763.1 link	n.685T>G	non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
ERICH2-DT	ENST00000663207.2 link	n.554T>G	non_coding_transcript_exon_variant	Exon 2 of 2
GAD1	ENST00000454603.5 link	c.-63-2259A>C	intron_variant	Intron 1 of 3	4	ENSP00000402366.1	C9JLZ7
GAD1	ENST00000445006.5 link	c.-385+14A>C	intron_variant	Intron 1 of 3	4	ENSP00000394948.1	C9JN45

Frequencies

GnomAD3 genomes

AF:

0.356

AC:

54053

AN:

151938

Hom.:

10195

Cov.:

show subpopulations

Gnomad AFR

AF:

0.221

Gnomad AMI

AF:

0.475

Gnomad AMR

AF:

0.377

Gnomad ASJ

AF:

0.404

Gnomad EAS

AF:

0.215

Gnomad SAS

AF:

0.358

Gnomad FIN

AF:

0.407

Gnomad MID

AF:

0.322

Gnomad NFE

AF:

0.431

Gnomad OTH

AF:

0.378

GnomAD4 exome

AF:

0.411

AC:

AN:

190

Hom.:

Cov.:

AF XY:

0.475

AC XY:

AN XY:

122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.393

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.393

AC:

AN:

112

Other (OTH)

AF:

0.900

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.355

AC:

54053

AN:

152054

Hom.:

10191

Cov.:

AF XY:

0.355

AC XY:

26372

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.220

AC:

9141

AN:

41490

American (AMR)

AF:

0.376

AC:

5756

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.404

AC:

1399

AN:

3462

East Asian (EAS)

AF:

0.213

AC:

1098

AN:

5146

South Asian (SAS)

AF:

0.360

AC:

1731

AN:

4810

European-Finnish (FIN)

AF:

0.407

AC:

4294

AN:

10562

Middle Eastern (MID)

AF:

0.324

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.431

AC:

29313

AN:

67980

Other (OTH)

AF:

0.377

AC:

796

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1801

3602

5402

7203

9004

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

524

1048

1572

2096

2620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.404

Hom.:

2689

Bravo

AF:

0.346

Asia WGS

AF:

0.307

AC:

1070

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

0.65

PromoterAI

0.044

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over