NM_000170.3:c.660C>T

Variant names:

• chr9-6606645-G-A
• rs2228095
• NM_000170.3:c.660C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000170.3(GLDC):​c.660C>T​(p.Leu220Leu) 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:6
• Conservation: PhyloP100: 0.491
• Publications: 4 publications found

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]

GLDC Gene-Disease associations (from GenCC):

• glycine encephalopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen
• glycine encephalopathy 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atypical glycine encephalopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000170.3. 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
	GLDC	NM_000170.3	MANE Select	c.660C>T	p.Leu220Leu	synonymous	Exon 5 of 25	NP_000161.2	P23378

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	ENST00000321612.8	TSL:1 MANE Select	c.660C>T	p.Leu220Leu	synonymous	Exon 5 of 25	ENSP00000370737.4	P23378
	GLDC	ENST00000920236.1		c.660C>T	p.Leu220Leu	synonymous	Exon 5 of 25	ENSP00000590295.1
	GLDC	ENST00000953081.1		c.660C>T	p.Leu220Leu	synonymous	Exon 5 of 26	ENSP00000623139.1

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

GnomAD2 exomes AF: 0.0206 AC: 5181 AN: 251478 AF XY: 0.0173

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 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

African (AFR) AF: 0.226 AC: 7377 AN: 32610

American (AMR) AF: 0.0131 AC: 587 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 82 AN: 26074

East Asian (EAS) AF: 0.000933 AC: 37 AN: 39656

South Asian (SAS) AF: 0.0190 AC: 1633 AN: 85976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.0148 AC: 85 AN: 5750

European-Non Finnish (NFE) AF: 0.000590 AC: 652 AN: 1104972

Other (OTH) AF: 0.0184 AC: 1105 AN: 60048

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

African (AFR) AF: 0.227 AC: 9402 AN: 41488

American (AMR) AF: 0.0287 AC: 439 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5180

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.000971 AC: 66 AN: 68006

Other (OTH) AF: 0.0564 AC: 119 AN: 2110

Alfa AF: 0.0578 Hom.: 551

Bravo AF: 0.0751

Asia WGS AF: 0.0600 AC: 209 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycine encephalopathy (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.2
DANN	Benign	0.57
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2228095; hg19: chr9-6606645; COSMIC: COSV58682430; COSMIC: COSV58682430;