2-210204643-C-A

Variant names:

• chr2-210204643-C-A
• rs1688854112
• NM_001608.4:c.808G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001608.4(ACADL):​c.808G>T​(p.Ala270Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACADL NM_001608.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

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]

ENSG00000279317 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADL	NM_001608.4	c.808G>T	p.Ala270Ser	missense_variant	Exon 7 of 11	ENST00000233710.4	NP_001599.1
ACADL	XM_005246517.5	c.745G>T	p.Ala249Ser	missense_variant	Exon 7 of 11		XP_005246574.1
ACADL	XM_047444103.1	c.385G>T	p.Ala129Ser	missense_variant	Exon 7 of 11		XP_047300059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADL	ENST00000233710.4	c.808G>T	p.Ala270Ser	missense_variant	Exon 7 of 11	1	NM_001608.4	ENSP00000233710.3
ACADL	ENST00000652584.1	n.1036G>T		non_coding_transcript_exon_variant	Exon 7 of 11
ENSG00000279317	ENST00000412065.1	n.313-13829C>A		intron_variant	Intron 1 of 2	4
ENSG00000279317	ENST00000639259.2	n.280-25640C>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.808G>T (p.A270S) alteration is located in exon 7 (coding exon 7) of the ACADL gene. This alteration results from a G to T substitution at nucleotide position 808, causing the alanine (A) at amino acid position 270 to be replaced by a serine (S). 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	Benign	0.089
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.49
Sift	Benign	0.070	T
Sift4G	Benign	0.11	T
Polyphen		0.012	B
Vest4		0.50
MutPred		0.46		Gain of phosphorylation at A270 (P = 0.0371);
MVP		0.96
MPC		0.21
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.31
gMVP		0.51

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

Other links and lift over

dbSNP: rs1688854112; hg19: chr2-211069367;