12-39604065-G-T

Variant names:

• chr12-39604065-G-T
• rs12228617
• NM_005164.4:c.1406-59C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005164.4(ABCD2):​c.1406-59C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,201,426 control chromosomes in the GnomAD database, including 24,542 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (7207 hom., cov: 32)
  • Exomes 𝑓: 0.17 (17335 hom.)
• Consequence: ABCD2 NM_005164.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.169
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD2	NM_005164.4	MANE Select	c.1406-59C>A		intron	N/A	NP_005155.1
	ABCD2	NM_001412788.1		c.1406-59C>A		intron	N/A	NP_001399717.1
	ABCD2	NM_001412789.1		c.1406-59C>A		intron	N/A	NP_001399718.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCD2	ENST00000308666.4	TSL:1 MANE Select	c.1406-59C>A		intron	N/A	ENSP00000310688.3

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40248 AN: 151682 Hom.: 7177 Cov.: 32

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.245

GnomAD4 exome AF: 0.168 AC: 175813 AN: 1049626 Hom.: 17335 AF XY: 0.166 AC XY: 89538 AN XY: 540012

African (AFR) AF: 0.518 AC: 12407 AN: 23948

American (AMR) AF: 0.123 AC: 4949 AN: 40172

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 3887 AN: 22656

East Asian (EAS) AF: 0.174 AC: 6462 AN: 37102

South Asian (SAS) AF: 0.150 AC: 11090 AN: 74104

European-Finnish (FIN) AF: 0.158 AC: 8054 AN: 51086

Middle Eastern (MID) AF: 0.162 AC: 727 AN: 4488

European-Non Finnish (NFE) AF: 0.160 AC: 119689 AN: 749620

Other (OTH) AF: 0.184 AC: 8548 AN: 46450

GnomAD4 genome AF: 0.266 AC: 40326 AN: 151800 Hom.: 7207 Cov.: 32 AF XY: 0.262 AC XY: 19453 AN XY: 74164

African (AFR) AF: 0.516 AC: 21355 AN: 41346

American (AMR) AF: 0.180 AC: 2743 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 634 AN: 3468

East Asian (EAS) AF: 0.177 AC: 914 AN: 5168

South Asian (SAS) AF: 0.153 AC: 737 AN: 4824

European-Finnish (FIN) AF: 0.157 AC: 1654 AN: 10542

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11553 AN: 67890

Other (OTH) AF: 0.248 AC: 521 AN: 2102

Alfa AF: 0.131 Hom.: 311

Bravo AF: 0.279

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.82
DANN	Benign	0.29
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs12228617; hg19: chr12-39997867; COSMIC: COSV58050384;