rs63750759

chr16-16154974-G-Achr16-16154974-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM5 PP5_Very_Strong BP4

The NM_001171.6(ABCC6):c.3940C>T(p.Arg1314Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,576,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R1314Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.32

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 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001171.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-16154973-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2036896.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 16-16154974-G-A is Pathogenic according to our data. Variant chr16-16154974-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16154974-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3097675).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.3940C>T	p.Arg1314Trp	missense_variant	28/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.3598C>T	p.Arg1200Trp	missense_variant	28/31
ABCC6	NR_147784.1	n.3602C>T		non_coding_transcript_exon_variant	26/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.3940C>T	p.Arg1314Trp	missense_variant	28/31	1	NM_001171.6	P1
ABCC6	ENST00000576204.6	n.803C>T		non_coding_transcript_exon_variant	1/2	5
ABCC6	ENST00000456970.6	c.*949C>T		3_prime_UTR_variant, NMD_transcript_variant	26/29	2
ABCC6	ENST00000622290.5	c.*112C>T		3_prime_UTR_variant, NMD_transcript_variant	29/32	5

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152108 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000189 AC: 35 AN: 184926 Hom.: 0 AF XY: 0.0000904 AC XY: 9 AN XY: 99530

Gnomad AFR exome AF: 0.00218

Gnomad AMR exome AF: 0.0000714

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000363

Gnomad SAS exome AF: 0.0000807

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000259

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000793 AC: 113 AN: 1424726 Hom.: 0 Cov.: 32 AF XY: 0.0000723 AC XY: 51 AN XY: 705360

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.000102

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000133

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000914

Gnomad4 OTH exome AF: 0.000135

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152226 Hom.: 0 Cov.: 31 AF XY: 0.000564 AC XY: 42 AN XY: 74426

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000251 Hom.: 0

Bravo AF: 0.000672

ESP6500AA AF: 0.000686 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000216 AC: 26

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 13, 2012	- -
Pathogenic, no assertion criteria provided	research	PXE International	Mar 01, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2022	Published functional studies demonstrate a damaging effect with R1314W resulting in abnormal protein trafficking and inappropriate intracellular accumulation (Le Saux et al., 2011); 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: 16392638, 22209248, 10835642, 30537162, 34205333, 34906475, 21935449, 24008425, 19339160, 24352041, 23483032, 27994049, 28102862, 28416300, 27826008, 32445016, 31589614, 34440381, 33005041, 32873932) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1314 of the ABCC6 protein (p.Arg1314Trp). This variant is present in population databases (rs63750759, gnomAD 0.3%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 10835642, 16835894, 19339160, 30537162). ClinVar contains an entry for this variant (Variation ID: 6564). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCC6 function (PMID: 21935449, 23483032, 27994049). This variant disrupts the p.Arg1314 amino acid residue in ABCC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29722917). 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. -

Arterial calcification, generalized, of infancy, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 13, 2012

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.5	D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.98
MVP		0.96
MPC		0.42
ClinPred		0.33	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs63750759; hg19: chr16-16248831; COSMIC: COSV52742951;