2-210203444-C-T

Position:

chr2-210203444-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The ENST00000233710.4(ACADL):c.871G>A(p.Glu291Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,607,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

ACADL
ENST00000233710.4 missense, splice_region

Scores

Splicing: ADA: 0.9936

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a active_site Proton acceptor (size 0) in uniprot entity ACADL_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ACADL	NM_001608.4 linkuse as main transcript	c.871G>A	p.Glu291Lys	missense_variant, splice_region_variant	8/11	ENST00000233710.4	NP_001599.1
ACADL	XM_005246517.5 linkuse as main transcript	c.808G>A	p.Glu270Lys	missense_variant, splice_region_variant	8/11		XP_005246574.1
ACADL	XM_047444103.1 linkuse as main transcript	c.448G>A	p.Glu150Lys	missense_variant, splice_region_variant	8/11		XP_047300059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ACADL	ENST00000233710.4 linkuse as main transcript	c.871G>A	p.Glu291Lys	missense_variant, splice_region_variant	8/11	1	NM_001608.4	ENSP00000233710	P1
	ENST00000639259.2 linkuse as main transcript	n.280-26839C>T		intron_variant, non_coding_transcript_variant		5
ACADL	ENST00000652584.1 linkuse as main transcript	n.1099G>A		splice_region_variant, non_coding_transcript_exon_variant	8/11
	ENST00000412065.1 linkuse as main transcript	n.313-15028C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248366

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134282

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:

0.0000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000261

AC:

AN:

1455354

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

724212

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:

0.0000334

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.871G>A (p.E291K) 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 871, causing the glutamic acid (E) at amino acid position 291 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.017

Polyphen

0.25

Vest4

0.95

MutPred

0.90

Gain of methylation at E291 (P = 0.0224);

MVP

0.99

MPC

0.57

ClinPred

1.0

GERP RS

5.4

Varity_R

0.98

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.10

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