chr2-210203383-C-A

Variant names:

• chr2-210203383-C-A
• rs377085604
• NM_001608.4:c.932G>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001608.4(ACADL):​c.932G>T​(p.Arg311Met) variant causes a missense change. The variant allele was found at a frequency of 0.00678 in 1,611,594 control chromosomes in the GnomAD database, including 52 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 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (50 hom.)
• Consequence: ACADL NM_001608.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.60
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• long chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000279317 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0887534).
• BP6: Variant 2-210203383-C-A is Benign according to our data. Variant chr2-210203383-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 439352.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001608.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADL	NM_001608.4	MANE Select	c.932G>T	p.Arg311Met	missense	Exon 8 of 11	NP_001599.1	P28330

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADL	ENST00000233710.4	TSL:1 MANE Select	c.932G>T	p.Arg311Met	missense	Exon 8 of 11	ENSP00000233710.3	P28330
	ACADL	ENST00000862330.1		c.899G>T	p.Arg300Met	missense	Exon 8 of 11	ENSP00000532389.1
	ACADL	ENST00000862329.1		c.794G>T	p.Arg265Met	missense	Exon 7 of 10	ENSP00000532388.1

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 780 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00745

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00155 AC: 387 AN: 248982 AF XY: 0.00165

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000815

Gnomad ASJ exome AF: 0.000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00329

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00695 AC: 10146 AN: 1459306 Hom.: 50 Cov.: 30 AF XY: 0.00667 AC XY: 4845 AN XY: 725970

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000748 AC: 25 AN: 33442

American (AMR) AF: 0.00244 AC: 109 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 54 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00383 AC: 330 AN: 86204

European-Finnish (FIN) AF: 0.0103 AC: 551 AN: 53254

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.00784 AC: 8700 AN: 1109960

Other (OTH) AF: 0.00615 AC: 371 AN: 60288

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00512 AC: 780 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.00513 AC XY: 382 AN XY: 74456

African (AFR) AF: 0.00130 AC: 54 AN: 41566

American (AMR) AF: 0.00491 AC: 75 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.0111 AC: 118 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00745 AC: 507 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00500 Hom.: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00194 AC: 235

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Long chain acyl-CoA dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Benign	0.93
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.089	T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.6	L
PhyloP100		5.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.74
Sift	Benign	0.061	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.80
MVP		0.99
MPC		0.89
ClinPred		0.022	T
GERP RS		5.4
Varity_R		0.51
gMVP		0.83
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs377085604; hg19: chr2-211068107; COSMIC: COSV52052459;