rs2228095

chr9-6606645-G-Achr9-6606645-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000170.3(GLDC):c.660C>T(p.Leu220=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,605,400 control chromosomes in the GnomAD database, including 2,090 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (1112 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (978 hom.)
• Consequence: GLDC NM_000170.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.491

Genes affected

GLDC (HGNC:4313): (glycine decarboxylase) Degradation of glycine is brought about by the glycine cleavage system, which is composed of four mitochondrial protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). The protein encoded by this gene is the P protein, which binds to glycine and enables the methylamine group from glycine to be transferred to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH).[provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 9-6606645-G-A is Benign according to our data. Variant chr9-6606645-G-A is described in ClinVar as [Benign]. Clinvar id is 367202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.491 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3	c.660C>T	p.Leu220=	synonymous_variant	5/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8	c.660C>T	p.Leu220=	synonymous_variant	5/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes AF: 0.0662 AC: 10074 AN: 152070 Hom.: 1089 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.0522

GnomAD3 exomes AF: 0.0206 AC: 5181 AN: 251478 Hom.: 454 AF XY: 0.0173 AC XY: 2345 AN XY: 135916

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00245

Gnomad SAS exome AF: 0.0236

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.00795 AC: 11558 AN: 1453212 Hom.: 978 Cov.: 28 AF XY: 0.00762 AC XY: 5516 AN XY: 723642

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.0131

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.000933

Gnomad4 SAS exome AF: 0.0190

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000590

Gnomad4 OTH exome AF: 0.0184

GnomAD4 genome AF: 0.0667 AC: 10149 AN: 152188 Hom.: 1112 Cov.: 32 AF XY: 0.0652 AC XY: 4850 AN XY: 74422

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.0287

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.0564

Alfa AF: 0.0294 Hom.: 226

Bravo AF: 0.0751

Asia WGS AF: 0.0600 AC: 209 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00160

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Non-ketotic hyperglycinemia Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 29, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2018

This variant is associated with the following publications: (PMID: 16601880) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	4.2
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2228095; hg19: chr9-6606645; COSMIC: COSV58682430; COSMIC: COSV58682430;