12-39573859-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005164.4(ABCD2):c.1878-18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00833 in 1,603,096 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0068 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (111 hom.)
• Consequence: ABCD2 NM_005164.4 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0390

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-39573859-C-G is Benign according to our data. Variant chr12-39573859-C-G is described in ClinVar as [Benign]. Clinvar id is 559119.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00685 (1042/152162) while in subpopulation SAS AF= 0.0247 (119/4824). AF 95% confidence interval is 0.0211. There are 7 homozygotes in gnomad4. There are 544 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCD2	NM_005164.4	c.1878-18G>C		intron_variant		ENST00000308666.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCD2	ENST00000308666.4	c.1878-18G>C		intron_variant		1	NM_005164.4	P1

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1041 AN: 152044 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00879

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00851 AC: 2070 AN: 243240 Hom.: 29 AF XY: 0.00959 AC XY: 1261 AN XY: 131458

Gnomad AFR exome AF: 0.000870

Gnomad AMR exome AF: 0.00265

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.000608

Gnomad SAS exome AF: 0.0272

Gnomad FIN exome AF: 0.00252

Gnomad NFE exome AF: 0.00870

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.00848 AC: 12306 AN: 1450934 Hom.: 111 Cov.: 29 AF XY: 0.00906 AC XY: 6538 AN XY: 721418

Gnomad4 AFR exome AF: 0.00100

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.00993

Gnomad4 EAS exome AF: 0.000203

Gnomad4 SAS exome AF: 0.0264

Gnomad4 FIN exome AF: 0.00265

Gnomad4 NFE exome AF: 0.00809

Gnomad4 OTH exome AF: 0.00837

GnomAD4 genome AF: 0.00685 AC: 1042 AN: 152162 Hom.: 7 Cov.: 32 AF XY: 0.00731 AC XY: 544 AN XY: 74384

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0247

Gnomad4 FIN AF: 0.00255

Gnomad4 NFE AF: 0.00879

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00687 Hom.: 0

Bravo AF: 0.00637

Asia WGS AF: 0.0120 AC: 41 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 06, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.4
Dann	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs139846202; hg19: chr12-39967661;