19-12891188-G-C

Variant names:

• chr19-12891188-G-C
• rs886054240
• ENST00000590627.5:n.9G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000590627.5(GCDH):​n.9G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000065 in 614,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: GCDH ENST00000590627.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.33
• Publications: 0 publications found

Genes affected

GCDH (HGNC:4189): (glutaryl-CoA dehydrogenase) The protein encoded by this gene belongs to the acyl-CoA dehydrogenase family. It catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. The enzyme exists in the mitochondrial matrix as a homotetramer of 45-kD subunits. Mutations in this gene result in the metabolic disorder glutaric aciduria type 1, which is also known as glutaric acidemia type I. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 12. [provided by RefSeq, Mar 2013]

GCDH Gene-Disease associations (from GenCC):

• glutaryl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, Myriad Women’s Health

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCDH	NM_000159.4	c.-49G>C		5_prime_UTR_variant	Exon 1 of 12	ENST00000222214.10	NP_000150.1
GCDH	NR_102316.1	n.60G>C		non_coding_transcript_exon_variant	Exon 1 of 12
GCDH	NR_102317.1	n.60G>C		non_coding_transcript_exon_variant	Exon 1 of 11
GCDH	NM_013976.5	c.-49G>C		5_prime_UTR_variant	Exon 1 of 12		NP_039663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.-49G>C		5_prime_UTR_variant	Exon 1 of 12	1	NM_000159.4	ENSP00000222214.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000650 AC: 4 AN: 614992 Hom.: 0 Cov.: 8 AF XY: 0.0000123 AC XY: 4 AN XY: 326076

African (AFR) AF: 0.00 AC: 0 AN: 17018

American (AMR) AF: 0.00 AC: 0 AN: 34388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20136

East Asian (EAS) AF: 0.00 AC: 0 AN: 32092

South Asian (SAS) AF: 0.0000154 AC: 1 AN: 64826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2566

European-Non Finnish (NFE) AF: 0.00000793 AC: 3 AN: 378172

Other (OTH) AF: 0.00 AC: 0 AN: 32166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.35
DANN	Benign	0.64
PhyloP100		-2.3
PromoterAI		0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs886054240; hg19: chr19-13002002;