2-170816824-T-C

Variant names:

• chr2-170816824-T-C
• rs754019434
• ENST00000375272.5:c.-292T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The ENST00000375272.5(GAD1):​c.-292T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 151,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GAD1 ENST00000375272.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.482
• Publications: 0 publications found

Genes affected

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]

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

GAD1-AS1 (HGNC:40250):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000237 (36/151876) while in subpopulation NFE AF = 0.000442 (30/67918). AF 95% confidence interval is 0.000317. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375272.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1-AS1	NR_197761.1		n.643+30A>G		intron	N/A
	GAD1-AS1	NR_197762.1		n.412+30A>G		intron	N/A
	GAD1-AS1	NR_197763.1		n.469+30A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000375272.5	TSL:1	c.-292T>C		5_prime_UTR	Exon 1 of 7	ENSP00000364421.1	Q99259-3
	GAD1	ENST00000625689.2	TSL:5	c.-288T>C		5_prime_UTR	Exon 1 of 18	ENSP00000486612.1	Q99259-4
	GAD1	ENST00000445006.5	TSL:4	c.-288T>C		5_prime_UTR	Exon 2 of 4	ENSP00000394948.1	C9JN45

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151758 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000947

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000442

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2436 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1338

African (AFR) AF: 0.00 AC: 0 AN: 54

American (AMR) AF: 0.00 AC: 0 AN: 46

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 46

East Asian (EAS) AF: 0.00 AC: 0 AN: 256

South Asian (SAS) AF: 0.00 AC: 0 AN: 16

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1572

Other (OTH) AF: 0.00 AC: 0 AN: 130

GnomAD4 genome AF: 0.000237 AC: 36 AN: 151876 Hom.: 0 Cov.: 31 AF XY: 0.000229 AC XY: 17 AN XY: 74208

African (AFR) AF: 0.000121 AC: 5 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.0000947 AC: 1 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000442 AC: 30 AN: 67918

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000242

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.93
PhyloP100		0.48
PromoterAI		-0.28	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs754019434; hg19: chr2-171673334;