rs58760581

Variant names:

• chr16-16154619-C-T
• rs58760581
• NM_001171.6:c.4208+9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001171.6(ABCC6):​c.4208+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,611,610 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 31)
  • Exomes 𝑓: 0.018 (329 hom.)
• Consequence: ABCC6 NM_001171.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.37
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• arterial calcification, generalized, of infancy, 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• autosomal recessive inherited pseudoxanthoma elasticum

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• arterial calcification of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-16154619-C-T is Benign according to our data. Variant chr16-16154619-C-T is described in ClinVar as Benign. ClinVar VariationId is 433396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0122 (1850/152242) while in subpopulation SAS AF = 0.0415 (200/4820). AF 95% confidence interval is 0.0368. There are 18 homozygotes in GnomAd4. There are 900 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.4208+9G>A		intron_variant	Intron 29 of 30	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.4208+9G>A		intron_variant	Intron 29 of 30	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000456970.6	n.*1217+9G>A		intron_variant	Intron 27 of 28	2		ENSP00000405002.2
ABCC6	ENST00000622290.5	n.*380+9G>A		intron_variant	Intron 30 of 31	5		ENSP00000483331.2
ABCC6	ENST00000576204.6	n.*111G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1849 AN: 152124 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.0415

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0151 AC: 3735 AN: 246964 AF XY: 0.0172

Gnomad AFR exome AF: 0.00288

Gnomad AMR exome AF: 0.00539

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.000438

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0178 AC: 25980 AN: 1459368 Hom.: 329 Cov.: 31 AF XY: 0.0186 AC XY: 13499 AN XY: 725936

African (AFR) AF: 0.00269 AC: 90 AN: 33426

American (AMR) AF: 0.00530 AC: 237 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 384 AN: 26128

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39698

South Asian (SAS) AF: 0.0416 AC: 3586 AN: 86112

European-Finnish (FIN) AF: 0.0108 AC: 569 AN: 52864

Middle Eastern (MID) AF: 0.0353 AC: 151 AN: 4282

European-Non Finnish (NFE) AF: 0.0179 AC: 19912 AN: 1111932

Other (OTH) AF: 0.0173 AC: 1042 AN: 60214

GnomAD4 genome AF: 0.0122 AC: 1850 AN: 152242 Hom.: 18 Cov.: 31 AF XY: 0.0121 AC XY: 900 AN XY: 74444

African (AFR) AF: 0.00318 AC: 132 AN: 41562

American (AMR) AF: 0.00804 AC: 123 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5162

South Asian (SAS) AF: 0.0415 AC: 200 AN: 4820

European-Finnish (FIN) AF: 0.0141 AC: 150 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0170 AC: 1158 AN: 67998

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.0142 Hom.: 9

Bravo AF: 0.0105

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0197

EpiControl AF: 0.0199

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive inherited pseudoxanthoma elasticum Benign:2

Mar 01, 2021

PXE International

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.015
DANN	Benign	0.60
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs58760581; hg19: chr16-16248476;