10-26217930-C-T

Variant names:

• chr10-26217930-C-T
• rs2229845
• NM_001134366.2:c.225C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001134366.2(GAD2):​c.225C>T​(p.Cys75Cys) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.778
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -19 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_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 455 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAD2	NM_001134366.2	c.225C>T	p.Cys75Cys	synonymous_variant	Exon 3 of 16	ENST00000376261.8	NP_001127838.1
GAD2	NM_000818.3	c.225C>T	p.Cys75Cys	synonymous_variant	Exon 3 of 17		NP_000809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAD2	ENST00000376261.8	c.225C>T	p.Cys75Cys	synonymous_variant	Exon 3 of 16	1	NM_001134366.2	ENSP00000365437.3
GAD2	ENST00000259271.7	c.225C>T	p.Cys75Cys	synonymous_variant	Exon 3 of 17	1		ENSP00000259271.3
GAD2	ENST00000428517.2	n.225C>T		non_coding_transcript_exon_variant	Exon 3 of 4	1		ENSP00000390434.2
GAD2	ENST00000648567.1	c.-118C>T		5_prime_UTR_variant	Exon 3 of 17			ENSP00000498009.1

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

GnomAD2 exomes AF: 0.00566 AC: 1382 AN: 244332 AF XY: 0.00432

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 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

African (AFR) AF: 0.000359 AC: 12 AN: 33410

American (AMR) AF: 0.0313 AC: 1395 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00625 AC: 163 AN: 26078

East Asian (EAS) AF: 0.00618 AC: 245 AN: 39662

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86194

European-Finnish (FIN) AF: 0.00180 AC: 94 AN: 52360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000225 AC: 250 AN: 1111170

Other (OTH) AF: 0.00196 AC: 118 AN: 60294

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

African (AFR) AF: 0.000962 AC: 40 AN: 41588

American (AMR) AF: 0.0198 AC: 303 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00620 AC: 32 AN: 5158

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68020

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.1
DANN	Benign	0.91
PhyloP100		0.78
Mutation Taster		=99/1	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: rs2229845; hg19: chr10-26506859; COSMIC: COSV52165177; COSMIC: COSV52165177;