chr16-48244582-A-C

Variant names:

• chr16-48244582-A-C
• rs1006824665
• NM_031490.5:c.194A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031490.5(LONP2):​c.194A>C​(p.Asp65Ala) variant causes a 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D65H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LONP2 NM_031490.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.65
• Publications: 0 publications found

Genes affected

LONP2 (HGNC:20598): (lon peptidase 2, peroxisomal) In human, peroxisomes function primarily to catalyze fatty acid beta-oxidation and, as a by-product, produce hydrogen peroxide and superoxide. The protein encoded by this gene is an ATP-dependent protease that likely plays a role in maintaining overall peroxisome homeostasis as well as proteolytically degrading peroxisomal proteins damaged by oxidation. The protein has an N-terminal Lon N substrate recognition domain, an ATPase domain, a proteolytic domain, and, in some isoforms, a C-terminal peroxisome targeting sequence. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2017]

ABCC11 (HGNC:14639): (ATP binding cassette subfamily C member 11) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This ABC full transporter is a member of the MRP subfamily which is involved in multi-drug resistance. The product of this gene participates in physiological processes involving bile acids, conjugated steroids, and cyclic nucleotides. In addition, a SNP in this gene is responsible for determination of human earwax type. This gene and family member ABCC12 are determined to be derived by duplication and are both localized to chromosome 16q12.1. Multiple alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031490.5. 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
	LONP2	NM_031490.5	MANE Select	c.194A>C	p.Asp65Ala	missense	Exon 1 of 15	NP_113678.2
	ABCC11	NM_001370497.1	MANE Select	c.-19+2732T>G		intron	N/A	NP_001357426.1	Q96J66-1
	LONP2	NM_001348078.2		c.194A>C	p.Asp65Ala	missense	Exon 1 of 17	NP_001335007.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LONP2	ENST00000285737.9	TSL:1 MANE Select	c.194A>C	p.Asp65Ala	missense	Exon 1 of 15	ENSP00000285737.4	Q86WA8-1
	LONP2	ENST00000535754.5	TSL:1	c.194A>C	p.Asp65Ala	missense	Exon 1 of 14	ENSP00000445426.1	Q86WA8-2
	ABCC11	ENST00000356608.7	TSL:1 MANE Select	c.-19+2732T>G		intron	N/A	ENSP00000349017.2	Q96J66-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000298 AC: 4 AN: 1343572 Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1 AN XY: 661806

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

African (AFR) AF: 0.00 AC: 0 AN: 28050

American (AMR) AF: 0.00 AC: 0 AN: 29768

Ashkenazi Jewish (ASJ) AF: 0.0000421 AC: 1 AN: 23780

East Asian (EAS) AF: 0.00 AC: 0 AN: 30450

South Asian (SAS) AF: 0.00 AC: 0 AN: 74540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4252

European-Non Finnish (NFE) AF: 0.00000284 AC: 3 AN: 1057204

Other (OTH) AF: 0.00 AC: 0 AN: 55802

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0129288), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.26
Sift	Benign	0.29	T
Sift4G	Benign	0.27	T
Polyphen		1.0	D
Vest4		0.58
MutPred		0.47		Loss of helix (P = 0.0237)
MVP		0.74
MPC		1.9
ClinPred		0.76	D
GERP RS		5.2
PromoterAI		-0.10	Neutral
Varity_R		0.35
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1006824665; hg19: chr16-48278493; COSMIC: COSV53520963;