rs2286963

Positions:

• chr2-210195326-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001608.4(ACADL):​c.997A>C​(p.Lys333Gln) variant causes a missense change. The variant allele was found at a frequency of 0.329 in 1,610,748 control chromosomes in the GnomAD database, including 90,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (6325 hom., cov: 32)
  • Exomes 𝑓: 0.33 (84208 hom.)
• Consequence: ACADL NM_001608.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 7.11

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032475889).
• BP6: Variant 2-210195326-T-G is Benign according to our data. Variant chr2-210195326-T-G is described in ClinVar as [Benign]. Clinvar id is 1620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADL	NM_001608.4	c.997A>C	p.Lys333Gln	missense_variant	9/11	ENST00000233710.4	NP_001599.1
ACADL	XM_005246517.5	c.934A>C	p.Lys312Gln	missense_variant	9/11		XP_005246574.1
ACADL	XM_047444103.1	c.574A>C	p.Lys192Gln	missense_variant	9/11		XP_047300059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADL	ENST00000233710.4	c.997A>C	p.Lys333Gln	missense_variant	9/11	1	NM_001608.4	ENSP00000233710	P1
	ENST00000639259.2	n.279+23497T>G		intron_variant, non_coding_transcript_variant		5
ACADL	ENST00000652584.1	n.1225A>C		non_coding_transcript_exon_variant	9/11
	ENST00000412065.1	n.313-23146T>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41476 AN: 152014 Hom.: 6324 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.394

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.279

GnomAD3 exomes AF: 0.301 AC: 75355 AN: 250752 Hom.: 11986 AF XY: 0.306 AC XY: 41490 AN XY: 135508

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.227

Gnomad ASJ exome AF: 0.285

Gnomad EAS exome AF: 0.204

Gnomad SAS exome AF: 0.312

Gnomad FIN exome AF: 0.358

Gnomad NFE exome AF: 0.348

Gnomad OTH exome AF: 0.309

GnomAD4 exome AF: 0.335 AC: 488328 AN: 1458618 Hom.: 84208 Cov.: 34 AF XY: 0.335 AC XY: 242788 AN XY: 725766

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.284

Gnomad4 EAS exome AF: 0.199

Gnomad4 SAS exome AF: 0.312

Gnomad4 FIN exome AF: 0.366

Gnomad4 NFE exome AF: 0.353

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.273 AC: 41472 AN: 152130 Hom.: 6325 Cov.: 32 AF XY: 0.271 AC XY: 20119 AN XY: 74358

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.252

Gnomad4 ASJ AF: 0.268

Gnomad4 EAS AF: 0.207

Gnomad4 SAS AF: 0.299

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.346

Gnomad4 OTH AF: 0.279

Alfa AF: 0.326 Hom.: 20156

Bravo AF: 0.260

TwinsUK AF: 0.350 AC: 1297

ALSPAC AF: 0.364 AC: 1402

ESP6500AA AF: 0.150 AC: 661

ESP6500EA AF: 0.341 AC: 2936

ExAC AF: 0.301 AC: 36504

Asia WGS AF: 0.241 AC: 838 AN: 3478

EpiCase AF: 0.336

EpiControl AF: 0.338

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Apr 11, 2014	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.6	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.0000015	P
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.64
Sift	Benign	0.051	T
Sift4G	Benign	0.071	T
Polyphen		0.98	D
Vest4		0.26
MPC		0.85
ClinPred		0.014	T
GERP RS		5.8
Varity_R		0.63
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs2286963; hg19: chr2-211060050; COSMIC: COSV52054667;