chr2-170816942-G-A

Variant names:

• chr2-170816942-G-A
• rs561714411
• NM_000817.3:c.-170G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS1

The NM_000817.3(GAD1):​c.-170G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 192,014 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: GAD1 NM_000817.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.70
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.14).
• BP6: Variant 2-170816942-G-A is Benign according to our data. Variant chr2-170816942-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 332217.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00023 (35/152338) while in subpopulation SAS AF = 0.00684 (33/4828). AF 95% confidence interval is 0.005. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000817.3. 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	NM_000817.3	MANE Select	c.-170G>A		5_prime_UTR	Exon 1 of 17	NP_000808.2	Q99259-1
	GAD1	NM_013445.4		c.-174G>A		5_prime_UTR	Exon 1 of 7	NP_038473.2
	GAD1-AS1	NR_197761.1		n.555C>T		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000358196.8	TSL:1 MANE Select	c.-170G>A		5_prime_UTR	Exon 1 of 17	ENSP00000350928.3	Q99259-1
	GAD1	ENST00000375272.5	TSL:1	c.-174G>A		5_prime_UTR	Exon 1 of 7	ENSP00000364421.1	Q99259-3
	GAD1	ENST00000625689.2	TSL:5	c.-170G>A		5_prime_UTR	Exon 1 of 18	ENSP00000486612.1	Q99259-4

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000252 AC: 1 AN: 39676 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 20796

African (AFR) AF: 0.00 AC: 0 AN: 984

American (AMR) AF: 0.00 AC: 0 AN: 904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1222

East Asian (EAS) AF: 0.00 AC: 0 AN: 4078

South Asian (SAS) AF: 0.00294 AC: 1 AN: 340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 188

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 25044

Other (OTH) AF: 0.00 AC: 0 AN: 2262

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74498

African (AFR) AF: 0.0000481 AC: 2 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

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	-0.14
CADD	Benign	18
DANN	Uncertain	0.97
PhyloP100		1.7
PromoterAI		0.056	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs561714411; hg19: chr2-171673452;