Variant 2-210203393-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001608.4(ACADL):c.922G>A(p.Glu308Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,453,142 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 1 hom. )

Consequence

ACADL
NM_001608.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.34

Variant links:

Genes affected

ACADL (HGNC:88): (acyl-CoA dehydrogenase long chain) The protein encoded by this gene belongs to the acyl-CoA dehydrogenase family, which is a family of mitochondrial flavoenzymes involved in fatty acid and branched chain amino-acid metabolism. This protein is one of the four enzymes that catalyze the initial step of mitochondrial beta-oxidation of straight-chain fatty acid. Defects in this gene are the cause of long-chain acyl-CoA dehydrogenase (LCAD) deficiency, leading to nonketotic hypoglycemia. [provided by RefSeq, Jul 2008]

ACADL links:

ENSG00000279317 (HGNC:):

ENSG00000279317 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADL	NM_001608.4 link	c.922G>A	p.Glu308Lys	missense_variant	8/11	ENST00000233710.4	NP_001599.1	P28330
ACADL	XM_005246517.5 link	c.859G>A	p.Glu287Lys	missense_variant	8/11		XP_005246574.1
ACADL	XM_047444103.1 link	c.499G>A	p.Glu167Lys	missense_variant	8/11		XP_047300059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ACADL	ENST00000233710.4 link	c.922G>A	p.Glu308Lys	missense_variant	8/11	1	NM_001608.4	ENSP00000233710.3	P28330
ACADL	ENST00000652584.1 link	n.1150G>A		non_coding_transcript_exon_variant	8/11
ENSG00000279317	ENST00000412065.1 link	n.313-15079C>T		intron_variant		4
ENSG00000279317	ENST00000639259.2 link	n.280-26890C>T		intron_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

249062

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134626

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000131

AC:

AN:

1453142

Hom.:

Cov.:

AF XY:

0.00000968

AC XY:

AN XY:

722984

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000163

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000549

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.922G>A (p.E308K) alteration is located in exon 8 (coding exon 8) of the ACADL gene. This alteration results from a G to A substitution at nucleotide position 922, causing the glutamic acid (E) at amino acid position 308 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

ACADL: PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.86

Sift

Benign

0.036

Sift4G

Benign

0.099

Polyphen

1.0

Vest4

0.87

MutPred

0.67

Gain of MoRF binding (P = 0.0044);

MVP

0.99

MPC

0.90

ClinPred

0.99

GERP RS

5.4

Varity_R

0.76

gMVP

0.90

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over