rs59513011

Positions:

chr16-16155055-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.965

Variant links:

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]

ABCC6 links:

ABCC6 (HGNC:):

ABCC6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 6 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
ABCC6	NM_001171.6 linkuse as main transcript	c.3883-24G>A	intron_variant	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 linkuse as main transcript	c.3541-24G>A	intron_variant		NP_001338729.1
ABCC6	NR_147784.1 linkuse as main transcript	n.3545-24G>A	intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.3883-24G>A	intron_variant		1	NM_001171.6	ENSP00000205557.7	O95255-1
ABCC6	ENST00000576204.6 linkuse as main transcript	n.722G>A	non_coding_transcript_exon_variant	1/2	5
ABCC6	ENST00000456970.6 linkuse as main transcript	n.*892-24G>A	intron_variant		2		ENSP00000405002.2	O95255-3
ABCC6	ENST00000622290.5 linkuse as main transcript	n.*55-24G>A	intron_variant		5		ENSP00000483331.2	A0A8C8Q0G8

Frequencies

GnomAD3 genomes

AF:

0.00503

AC:

765

AN:

152142

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00668

AC XY:

527

AN XY:

78896

show subpopulations

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.:

Cov.:

AF XY:

0.00595

AC XY:

4083

AN XY:

686634

show subpopulations

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.:

Cov.:

AF XY:

0.00517

AC XY:

385

AN XY:

74458

show subpopulations

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.:

Bravo

AF:

0.00480

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum

Benign:3

Benign, no assertion criteria provided	research	PXE International	Mar 01, 2021	- -
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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Arterial calcification, generalized, of infancy, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Pseudoxanthoma elasticum, forme fruste

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

ABCC6-related disorder

Benign:1

Benign, no assertion criteria provided

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over