rs59513011

chr16-16155055-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001171.6(ABCC6):c.3883-24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00564 in 1,544,704 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (56 hom.)
• Consequence: ABCC6 NM_001171.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.965

Genes affected

ABCC6 (HGNC:57): (ATP binding cassette subfamily C member 6) 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). The encoded protein, a member of the MRP subfamily, is involved in multi-drug resistance. Mutations in this gene cause pseudoxanthoma elasticum. Alternatively spliced transcript variants that encode different proteins have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-16155055-C-T is Benign according to our data. Variant chr16-16155055-C-T is described in ClinVar as [Benign]. Clinvar id is 433418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16155055-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00502 (765/152260) while in subpopulation SAS AF= 0.0114 (55/4820). AF 95% confidence interval is 0.009. There are 6 homozygotes in gnomad4. There are 385 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.3883-24G>A		intron_variant		ENST00000205557.12
ABCC6	NM_001351800.1	c.3541-24G>A		intron_variant
ABCC6	NR_147784.1	n.3545-24G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.3883-24G>A		intron_variant		1	NM_001171.6	P1
ABCC6	ENST00000576204.6	n.722G>A		non_coding_transcript_exon_variant	1/2	5
ABCC6	ENST00000456970.6	c.*892-24G>A		intron_variant, NMD_transcript_variant		2
ABCC6	ENST00000622290.5	c.*55-24G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 765 AN: 152142 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00638

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00604 AC: 892 AN: 147628 Hom.: 6 AF XY: 0.00668 AC XY: 527 AN XY: 78896

Gnomad AFR exome AF: 0.000486

Gnomad AMR exome AF: 0.00436

Gnomad ASJ exome AF: 0.00868

Gnomad EAS exome AF: 0.000265

Gnomad SAS exome AF: 0.0136

Gnomad FIN exome AF: 0.00232

Gnomad NFE exome AF: 0.00591

Gnomad OTH exome AF: 0.00741

GnomAD4 exome AF: 0.00571 AC: 7945 AN: 1392444 Hom.: 56 Cov.: 32 AF XY: 0.00595 AC XY: 4083 AN XY: 686634

Gnomad4 AFR exome AF: 0.000949

Gnomad4 AMR exome AF: 0.00428

Gnomad4 ASJ exome AF: 0.00792

Gnomad4 EAS exome AF: 0.000112

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.00218

Gnomad4 NFE exome AF: 0.00556

Gnomad4 OTH exome AF: 0.00651

GnomAD4 genome AF: 0.00502 AC: 765 AN: 152260 Hom.: 6 Cov.: 31 AF XY: 0.00517 AC XY: 385 AN XY: 74458

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00638

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00523 Hom.: 2

Bravo AF: 0.00480

Asia WGS AF: 0.00866 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Benign:3

Likely benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_007558.2(NM_001171.5):c.3883-24G>A in the ABCC6 gene has an allele frequency of 0.014 in South Asian subpopulation in the gnomAD database. Benign computational verdict because benign prediction from DANN. The variant was identified in a pseudoxanthoma elasticum patient (PMID: 16127278). Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1, BP4. -
Benign, no assertion criteria provided	research	PXE International	Mar 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	ABCC6: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ABCC6 c.3883-24G>A variant was identified in the literature in 1/81 families with pseudoxanthoma elasticum (PXE) (Miksch_2005_PMID:16086317). The variant was identified in dbSNP (ID: rs59513011) and ClinVar (classified as pathogenic by PXE International and likely benign by Reproductive Health Research and Development BGI Genomics). The variant was identified in control databases in 1003 of 178988 chromosomes (6 homozygous) at a frequency of 0.005604 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 310 of 22794 chromosomes (freq: 0.0136), Ashkenazi Jewish in 77 of 8704 chromosomes (freq: 0.008847), Other in 37 of 5406 chromosomes (freq: 0.006844), European (non-Finnish) in 421 of 72392 chromosomes (freq: 0.005816), Latino in 108 of 25632 chromosomes (freq: 0.004213), European (Finnish) in 35 of 14238 chromosomes (freq: 0.002458), African in 12 of 16932 chromosomes (freq: 0.000709), and East Asian in 3 of 12890 chromosomes (freq: 0.000233). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Pseudoxanthoma elasticum, forme fruste Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Arterial calcification, generalized, of infancy, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

ABCC6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.1
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs59513011; hg19: chr16-16248912;