rs63751215

Positions:

• chr16-16159556-G-A
• chr16-16159556-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_001171.6(ABCC6):​c.3661C>T​(p.Arg1221Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,968 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1221H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.28

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 283) in uniprot entity MRP6_HUMAN there are 90 pathogenic changes around while only 13 benign (87%) in NM_001171.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-16159555-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 433320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 16-16159556-G-A is Pathogenic according to our data. Variant chr16-16159556-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16159556-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.3661C>T	p.Arg1221Cys	missense_variant	26/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.3319C>T	p.Arg1107Cys	missense_variant	26/31
ABCC6	NR_147784.1	n.3323C>T		non_coding_transcript_exon_variant	24/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.3661C>T	p.Arg1221Cys	missense_variant	26/31	1	NM_001171.6	P1
ABCC6	ENST00000622290.5	c.3661C>T	p.Arg1221Cys	missense_variant, NMD_transcript_variant	26/32	5
ABCC6	ENST00000456970.6	c.*670C>T		3_prime_UTR_variant, NMD_transcript_variant	24/29	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251368 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461862 Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000837 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16086317, 25062064, 15727254, 16854481, 17617515, 15645653, 12673275) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 11, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1221 of the ABCC6 protein (p.Arg1221Cys). This variant is present in population databases (rs63751215, gnomAD 0.006%). This missense change has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 12673275, 15645653). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 433319). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC6 protein function. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1

Pathogenic, no assertion criteria provided

research

PXE International

Mar 01, 2021

- -

ABCC6-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2023

The ABCC6 c.3661C>T variant is predicted to result in the amino acid substitution p.Arg1221Cys. This variant has been reported in the compound heterozygous state in individuals with pseudoxanthoma elasticum (PX) ( Hu et al. 2003. PubMed ID: 12673275; Hu et al. 2004. PubMed ID: 15727254; Miksch et al. 2005. PubMed ID: 16086317; Pfender et al. 2007. PubMed ID: 17617515). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-16253413-G-A). In addition, an alternate change affecting the same amino acid, (p.Arg1221His) has been reported in the compound heterozygous state with the ABCC6 p.1141* variant in an individual with PXE (Kiec-Wilk et al. 2007. PubMed ID: 16854481), in the homozygous state in an individual with generalized calcification of infancy (GACI) (Nitschke et al. 2012. PubMed ID: 22209248), and has been reported as a pathogenic secondary (carrier) finding in an exome cohort (Capalbo et al. 2019. PubMed ID: 31589614). The c.3661C>T (p.Arg1221Cys) variant is interpreted as pathogenic. -

Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.0	D;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.87		Loss of MoRF binding (P = 9e-04);.;
MVP		0.95
MPC		0.47
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.82
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs63751215; hg19: chr16-16253413;