2-210203382-CCTGGT-AAACATAACATTCATG

Variant names:

• chr2-210203382-CCTGGT-AAACATAACATTCATG
• rs1559636157
• NM_001608.4:c.928_933delACCAGGinsCATGAATGTTATGTTT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001608.4(ACADL):​c.928_933delACCAGGinsCATGAATGTTATGTTT​(p.Thr310HisfsTer6) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACADL NM_001608.4 frameshift, missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.48

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-210203382-CCTGGT-AAACATAACATTCATG is Benign according to our data. Variant chr2-210203382-CCTGGT-AAACATAACATTCATG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 632339.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADL	NM_001608.4	c.928_933delACCAGGinsCATGAATGTTATGTTT	p.Thr310HisfsTer6	frameshift_variant, missense_variant	Exon 8 of 11	ENST00000233710.4	NP_001599.1
ACADL	XM_005246517.5	c.865_870delACCAGGinsCATGAATGTTATGTTT	p.Thr289HisfsTer6	frameshift_variant, missense_variant	Exon 8 of 11		XP_005246574.1
ACADL	XM_047444103.1	c.505_510delACCAGGinsCATGAATGTTATGTTT	p.Thr169HisfsTer6	frameshift_variant, missense_variant	Exon 8 of 11		XP_047300059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADL	ENST00000233710.4	c.928_933delACCAGGinsCATGAATGTTATGTTT	p.Thr310HisfsTer6	frameshift_variant, missense_variant	Exon 8 of 11	1	NM_001608.4	ENSP00000233710.3
ACADL	ENST00000652584.1	n.1156_1161delACCAGGinsCATGAATGTTATGTTT		non_coding_transcript_exon_variant	Exon 8 of 11
ENSG00000279317	ENST00000412065.1	n.313-15090_313-15085delCCTGGTinsAAACATAACATTCATG		intron_variant	Intron 1 of 2	4
ENSG00000279317	ENST00000639259.2	n.280-26901_280-26896delCCTGGTinsAAACATAACATTCATG		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Uncertain:1

Mar 16, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACADL c.928_933delACCAGGinsCATGAATGTTATGTTT (p.Thr310HisfsTer6) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance, but suspicious for pathogenicity for long-chain acyl-CoA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Benign:1

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1559636157; hg19: chr2-211068106;