10-26217930-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001134366.2(GAD2):c.225C>T(p.Cys75=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,611,790 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (30 hom.)
• Consequence: GAD2 NM_001134366.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.778

Genes affected

GAD2 (HGNC:4093): (glutamate decarboxylase 2) 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 autoantibody and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 10-26217930-C-T is Benign according to our data. Variant chr10-26217930-C-T is described in ClinVar as [Benign]. Clinvar id is 771432.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.778 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00299 (455/152316) while in subpopulation AMR AF= 0.0198 (303/15310). AF 95% confidence interval is 0.018. There are 6 homozygotes in gnomad4. There are 239 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 452 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAD2	NM_001134366.2	c.225C>T	p.Cys75=	synonymous_variant	3/16	ENST00000376261.8
GAD2	NM_000818.3	c.225C>T	p.Cys75=	synonymous_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAD2	ENST00000376261.8	c.225C>T	p.Cys75=	synonymous_variant	3/16	1	NM_001134366.2	P1
GAD2	ENST00000259271.7	c.225C>T	p.Cys75=	synonymous_variant	3/17	1		P1
GAD2	ENST00000428517.2	c.225C>T	p.Cys75=	synonymous_variant	3/4	1
GAD2	ENST00000648567.1	c.-118C>T		5_prime_UTR_variant	3/17

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 152198 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00619

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00566 AC: 1382 AN: 244332 Hom.: 21 AF XY: 0.00432 AC XY: 576 AN XY: 133320

Gnomad AFR exome AF: 0.000708

Gnomad AMR exome AF: 0.0313

Gnomad ASJ exome AF: 0.00706

Gnomad EAS exome AF: 0.00606

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.000471

Gnomad OTH exome AF: 0.00547

GnomAD4 exome AF: 0.00156 AC: 2280 AN: 1459474 Hom.: 30 Cov.: 32 AF XY: 0.00146 AC XY: 1057 AN XY: 725980

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.0313

Gnomad4 ASJ exome AF: 0.00625

Gnomad4 EAS exome AF: 0.00618

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00180

Gnomad4 NFE exome AF: 0.000225

Gnomad4 OTH exome AF: 0.00196

GnomAD4 genome AF: 0.00299 AC: 455 AN: 152316 Hom.: 6 Cov.: 32 AF XY: 0.00321 AC XY: 239 AN XY: 74478

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.0198

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00620

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.00454

Asia WGS AF: 0.00318 AC: 11 AN: 3474

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 18, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	7.1
Dann	Benign	0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229845; hg19: chr10-26506859; COSMIC: COSV52165177; COSMIC: COSV52165177;