2-210205678-C-G

Position:

chr2-210205678-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2

The NM_001608.4(ACADL):c.722G>C(p.Gly241Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,912 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 14 hom. )

Consequence

ACADL
NM_001608.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B: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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.09855232).

BP6

Variant 2-210205678-C-G is Benign according to our data. Variant chr2-210205678-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 593544.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr2-210205678-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00104 (1516/1461676) while in subpopulation MID AF= 0.0285 (164/5762). AF 95% confidence interval is 0.0249. There are 14 homozygotes in gnomad4_exome. There are 856 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADL	NM_001608.4 link	c.722G>C	p.Gly241Ala	missense_variant	6/11	ENST00000233710.4	NP_001599.1	P28330
ACADL	XM_005246517.5 link	c.659G>C	p.Gly220Ala	missense_variant	6/11		XP_005246574.1
ACADL	XM_047444103.1 link	c.299G>C	p.Gly100Ala	missense_variant	6/11		XP_047300059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ACADL	ENST00000233710.4 link	c.722G>C	p.Gly241Ala	missense_variant	6/11	1	NM_001608.4	ENSP00000233710.3	P28330
ACADL	ENST00000652584.1 link	n.950G>C		non_coding_transcript_exon_variant	6/11
ENSG00000279317	ENST00000412065.1 link	n.313-12794C>G		intron_variant		4
ENSG00000279317	ENST00000639259.2 link	n.280-24605C>G		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

158

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00353

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00180

AC:

451

AN:

251106

Hom.:

AF XY:

0.00204

AC XY:

277

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00275

Gnomad ASJ exome

AF:

0.00824

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00405

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000969

Gnomad OTH exome

AF:

0.00621

GnomAD4 exome

AF:

0.00104

AC:

1516

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

856

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.00275

Gnomad4 ASJ exome

AF:

0.00762

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00374

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000501

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00104

AC:

159

AN:

152236

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00236

Gnomad4 ASJ

AF:

0.00806

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00353

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00138

Hom.:

Bravo

AF:

0.00108

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00162

AC:

197

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long chain acyl-CoA dehydrogenase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Elsea Laboratory, Baylor College of Medicine

Apr 01, 2020

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 22, 2017

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

ACADL: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.64

MetaRNN

Benign

0.099

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.8

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MVP

0.99

MPC

0.87

ClinPred

0.14

GERP RS

5.3

Varity_R

0.90

gMVP

0.89

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