19-12896930-C-T

Variant names:

• chr19-12896930-C-T
• rs1328059662
• NM_000159.4:c.873C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_000159.4(GCDH):​c.873C>T​(p.Asn291Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GCDH NM_000159.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.95
• 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: Myriad Women’s Health, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-12896930-C-T is Benign according to our data. Variant chr19-12896930-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1764493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.95 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000159.4. 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
	GCDH	NM_000159.4	MANE Select	c.873C>T	p.Asn291Asn	synonymous	Exon 9 of 12	NP_000150.1	Q92947-1
	GCDH	NM_013976.5		c.873C>T	p.Asn291Asn	synonymous	Exon 9 of 12	NP_039663.1	Q92947-2
	GCDH	NR_102316.1		n.1036C>T		non_coding_transcript_exon	Exon 9 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCDH	ENST00000222214.10	TSL:1 MANE Select	c.873C>T	p.Asn291Asn	synonymous	Exon 9 of 12	ENSP00000222214.4	Q92947-1
	GCDH	ENST00000591470.5	TSL:1	c.873C>T	p.Asn291Asn	synonymous	Exon 8 of 11	ENSP00000466845.1	Q92947-1
	GCDH	ENST00000714069.1		c.873C>T	p.Asn291Asn	synonymous	Exon 9 of 13	ENSP00000519360.1	A0AAQ5BHD5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460960 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726840

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52696

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111852

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Glutaric aciduria, type 1 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.6
DANN	Benign	0.85
PhyloP100		1.9
PromoterAI		-0.0090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1328059662; hg19: chr19-13007744;