rs45617531

Variant names:

• chr2-170818553-A-C
• rs45617531
• NM_000817.3:c.-39A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000817.3(GAD1):​c.-39A>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 0.000938 in 1,582,168 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00077 (5 hom.)
• Consequence: GAD1 NM_000817.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.40
• Publications: 1 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]

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: Labcorp Genetics (formerly Invitae), G2P
• 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-AS1 (HGNC:40250):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-170818553-A-C is Benign according to our data. Variant chr2-170818553-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 893995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00252 (383/152242) while in subpopulation AMR AF = 0.00549 (84/15290). AF 95% confidence interval is 0.00455. There are 2 homozygotes in GnomAd4. There are 189 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.-39A>C		5_prime_UTR	Exon 2 of 17	NP_000808.2	Q99259-1
	GAD1	NM_013445.4		c.-39A>C		5_prime_UTR	Exon 2 of 7	NP_038473.2
	GAD1-AS1	NR_197761.1		n.99T>G		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAD1	ENST00000358196.8	TSL:1 MANE Select	c.-39A>C		5_prime_UTR	Exon 2 of 17	ENSP00000350928.3	Q99259-1
	GAD1	ENST00000375272.5	TSL:1	c.-39A>C		5_prime_UTR	Exon 2 of 7	ENSP00000364421.1	Q99259-3
	GAD1	ENST00000493875.5	TSL:1	n.-39A>C		non_coding_transcript_exon	Exon 1 of 17	ENSP00000434696.1	Q99259-4

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 384 AN: 152124 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00128 AC: 321 AN: 251020 AF XY: 0.00127

Gnomad AFR exome AF: 0.00561

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00517

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.000706

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000770 AC: 1101 AN: 1429926 Hom.: 5 Cov.: 26 AF XY: 0.000782 AC XY: 558 AN XY: 713590

African (AFR) AF: 0.00672 AC: 221 AN: 32872

American (AMR) AF: 0.00175 AC: 78 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00509 AC: 132 AN: 25924

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39508

South Asian (SAS) AF: 0.00100 AC: 86 AN: 85640

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53388

Middle Eastern (MID) AF: 0.00704 AC: 40 AN: 5682

European-Non Finnish (NFE) AF: 0.000366 AC: 396 AN: 1082842

Other (OTH) AF: 0.00209 AC: 124 AN: 59398

GnomAD4 genome AF: 0.00252 AC: 383 AN: 152242 Hom.: 2 Cov.: 31 AF XY: 0.00254 AC XY: 189 AN XY: 74432

African (AFR) AF: 0.00496 AC: 206 AN: 41550

American (AMR) AF: 0.00549 AC: 84 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68002

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00217 Hom.: 0

Bravo AF: 0.00295

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.78
CADD	Benign	12
DANN	Benign	0.72
PhyloP100		1.4
Mutation Taster		=299/1	polymorphism

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: rs45617531; hg19: chr2-171675063;