NM_001171.6:c.4015C>T

Variant names:

• chr16-16154899-G-A
• rs28939702
• NM_001171.6:c.4015C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_001171.6(ABCC6):​c.4015C>T​(p.Arg1339Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,611,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1339L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.960
• Publications: 24 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001171.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-16154898-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 265021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 16-16154899-G-A is Pathogenic according to our data. Variant chr16-16154899-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	NM_001171.6	MANE Select	c.4015C>T	p.Arg1339Cys	missense	Exon 28 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.3982C>T	p.Arg1328Cys	missense	Exon 28 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.3847C>T	p.Arg1283Cys	missense	Exon 27 of 30	NP_001427239.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.4015C>T	p.Arg1339Cys	missense	Exon 28 of 31	ENSP00000205557.7
	ABCC6	ENST00000456970.6	TSL:2	n.*1024C>T		non_coding_transcript_exon	Exon 26 of 29	ENSP00000405002.2
	ABCC6	ENST00000576204.6	TSL:5	n.878C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152080 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000825 AC: 20 AN: 242560 AF XY: 0.0000912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000554

Gnomad FIN exome AF: 0.0000982

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1459390 Hom.: 0 Cov.: 32 AF XY: 0.0000579 AC XY: 42 AN XY: 725804

African (AFR) AF: 0.0000599 AC: 2 AN: 33416

American (AMR) AF: 0.000203 AC: 9 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39560

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85684

European-Finnish (FIN) AF: 0.0000565 AC: 3 AN: 53112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111074

Other (OTH) AF: 0.0000995 AC: 6 AN: 60316

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152080 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74290

African (AFR) AF: 0.0000483 AC: 2 AN: 41408

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000537 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:5

Sep 10, 2024

PG23_Medical Genetics Lab, ASST Papa Giovanni XXIII

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 15, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;For recessive disorders, detected in trans with a pathogenic variant.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Mar 01, 2021

PXE International

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Oct 25, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v4: 77 heterozygotes, 0 homozygotes); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by clinical laboratories in ClinVar and reported in the literature in multiple individuals with pseudoxanthoma elasticum (PMIDs: 32873932, 10954200, 18253096, 15459974, 34906475). Additional information: Variant is predicted to result in a missense amino acid change from arginine to cysteine; This variant is homozygous; This gene is associated with autosomal recessive disease. Older publications suggest dominant disease (OMIM); Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4) (highest allele count: 32 heterozygotes, 0 homozygotes); Loss of function is a known mechanism of disease in this gene and is associated with generalized infantile arterial calcification 2 (MIM#614473) and pseudoxanthoma elasticum (PXE; MIM#264800); Variants in this gene are known to have variable expressivity. Intrafamilial variability with age-dependent severity has been well reported (PMID: 28102862); This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis).

not provided Pathogenic:2

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1339 of the ABCC6 protein (p.Arg1339Cys). This variant is present in population databases (rs28939702, gnomAD 0.02%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 10954200, 12384774). ClinVar contains an entry for this variant (Variation ID: 6576). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCC6 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCC6 function (PMID: 24352041, 27994049). This variant disrupts the p.Arg1339 amino acid residue in ABCC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16086317, 18157818). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Sep 07, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.21	N
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		0.96
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.88
MPC		0.47
ClinPred		0.70	D
GERP RS		-2.5
Varity_R		0.88
gMVP		0.95
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs28939702; hg19: chr16-16248756; COSMIC: COSV104567564;