chr16-16161567-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001171.6(ABCC6):c.3507-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,613,868 control chromosomes in the GnomAD database, including 357 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 31 hom., cov: 32)

Exomes 𝑓: 0.018 ( 326 hom. )

Consequence

ABCC6
NM_001171.6 splice_region, intron

Scores

Splicing: ADA: 0.02283

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 2.36

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 16-16161567-G-A is Benign according to our data. Variant chr16-16161567-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 281169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16161567-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-16161567-G-A is described in Lovd as [Benign]. Variant chr16-16161567-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0154 (2342/152296) while in subpopulation SAS AF= 0.0238 (115/4826). AF 95% confidence interval is 0.0203. There are 31 homozygotes in gnomad4. There are 1200 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 31 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ABCC6	NM_001171.6 link	c.3507-3C>T	splice_region_variant, intron_variant	Intron 24 of 30	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 link	c.3165-3C>T	splice_region_variant, intron_variant	Intron 24 of 30		NP_001338729.1
ABCC6	NR_147784.1 link	n.3169-3C>T	splice_region_variant, intron_variant	Intron 22 of 28

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCC6	ENST00000205557.12 link	c.3507-3C>T	splice_region_variant, intron_variant	Intron 24 of 30	1	NM_001171.6	ENSP00000205557.7	O95255-1
ABCC6	ENST00000456970.6 link	n.*516-3C>T	splice_region_variant, intron_variant	Intron 22 of 28	2		ENSP00000405002.2	O95255-3
ABCC6	ENST00000622290.5 link	n.3507-3C>T	splice_region_variant, intron_variant	Intron 24 of 31	5		ENSP00000483331.2	A0A8C8Q0G8

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2342

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00355

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0240

Gnomad FIN

AF:

0.0368

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0207

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.0164

AC:

4100

AN:

250166

Hom.:

AF XY:

0.0174

AC XY:

2354

AN XY:

135440

show subpopulations

Gnomad AFR exome

AF:

0.00315

Gnomad AMR exome

AF:

0.00868

Gnomad ASJ exome

AF:

0.0153

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0217

Gnomad FIN exome

AF:

0.0319

Gnomad NFE exome

AF:

0.0191

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0181

AC:

26517

AN:

1461572

Hom.:

326

Cov.:

AF XY:

0.0184

AC XY:

13359

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.00266

Gnomad4 AMR exome

AF:

0.00868

Gnomad4 ASJ exome

AF:

0.0152

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0218

Gnomad4 FIN exome

AF:

0.0305

Gnomad4 NFE exome

AF:

0.0189

Gnomad4 OTH exome

AF:

0.0173

GnomAD4 genome

AF:

0.0154

AC:

2342

AN:

152296

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1200

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00354

Gnomad4 AMR

AF:

0.0121

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0238

Gnomad4 FIN

AF:

0.0368

Gnomad4 NFE

AF:

0.0207

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0169

Hom.:

Bravo

AF:

0.0122

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0188

EpiControl

AF:

0.0187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCC6: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 13, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive inherited pseudoxanthoma elasticum

Benign:2

Mar 01, 2021

PXE International

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudoxanthoma elasticum, forme fruste

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arterial calcification, generalized, of infancy, 2

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Finnish congenital nephrotic syndrome

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous c.3507-3C>T variant in ABCC6 has been reported in at least 2 individuals with autosomal recessive pseudoxanthoma elasticum (PMID: 16835894). It has also been identified in >3% of European (Finnish) chromosomes and 14 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive pseudoxanthoma elasticum. -

Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2

Benign:1

Apr 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.023

dbscSNV1_RF

Benign

0.65

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