chr12-39586203-C-T

Variant names:

• chr12-39586203-C-T
• rs1941664166
• NM_005164.4:c.1741G>A

Variant summary

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

The NM_005164.4(ABCD2):​c.1741G>A​(p.Glu581Lys) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCD2 NM_005164.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31
• Publications: 0 publications found

Genes affected

ABCD2 (HGNC:66): (ATP binding cassette subfamily D member 2) 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 protein is a member of the ALD subfamily, which is involved in peroxisomal import of fatty acids and/or fatty acyl-CoAs in the organelle. All known peroxisomal ABC transporters are half transporters which require a partner half transporter molecule to form a functional homodimeric or heterodimeric transporter. The function of this peroxisomal membrane protein is unknown; however this protein is speculated to function as a dimerization partner of ABCD1 and/or other peroxisomal ABC transporters. Mutations in this gene have been observed in patients with adrenoleukodystrophy, a severe demyelinating disease. This gene has been identified as a candidate for a modifier gene, accounting for the extreme variation among adrenoleukodystrophy phenotypes. This gene is also a candidate for a complement group of Zellweger syndrome, a genetically heterogeneous disorder of peroxisomal biogenesis. [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_005164.4. 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
	ABCD2	NM_005164.4	MANE Select	c.1741G>A	p.Glu581Lys	missense	Exon 7 of 10	NP_005155.1	Q9UBJ2
	ABCD2	NM_001412788.1		c.1741G>A	p.Glu581Lys	missense	Exon 7 of 10	NP_001399717.1
	ABCD2	NM_001412789.1		c.1741G>A	p.Glu581Lys	missense	Exon 7 of 9	NP_001399718.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD2	ENST00000308666.4	TSL:1 MANE Select	c.1741G>A	p.Glu581Lys	missense	Exon 7 of 10	ENSP00000310688.3	Q9UBJ2
	ABCD2	ENST00000961978.1		c.1720G>A	p.Glu574Lys	missense	Exon 7 of 10	ENSP00000632037.1
	ABCD2	ENST00000961977.1		c.1609G>A	p.Glu537Lys	missense	Exon 6 of 9	ENSP00000632036.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.13	N
PhyloP100		7.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.47
Sift	Benign	0.30	T
Sift4G	Benign	0.31	T
Polyphen		0.57	P
Vest4		0.58
MutPred		0.43		Gain of ubiquitination at E581 (P = 0.0219)
MVP		0.93
MPC		0.93
ClinPred		0.93	D
GERP RS		3.7
Varity_R		0.34
gMVP		0.84
Mutation Taster		=83/17	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: rs1941664166; hg19: chr12-39980005;