rs63750428

chr16-16154767-G-Achr16-16154767-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM5 PP3_Strong PP5

The NM_001171.6(ABCC6):c.4069C>T(p.Arg1357Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000887 in 1,612,424 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1357Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:1
• Conservation: PhyloP100: 1.04

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 4) in uniprot entity MRP6_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001171.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-16154766-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2802563.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 16-16154767-G-A is Pathogenic according to our data. Variant chr16-16154767-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143119.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr16-16154767-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.4069C>T	p.Arg1357Trp	missense_variant	29/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.3727C>T	p.Arg1243Trp	missense_variant	29/31
ABCC6	NR_147784.1	n.3731C>T		non_coding_transcript_exon_variant	27/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.4069C>T	p.Arg1357Trp	missense_variant	29/31	1	NM_001171.6	P1
ABCC6	ENST00000576204.6	n.932C>T		non_coding_transcript_exon_variant	2/2	5
ABCC6	ENST00000456970.6	c.*1078C>T		3_prime_UTR_variant, NMD_transcript_variant	27/29	2
ABCC6	ENST00000622290.5	c.*241C>T		3_prime_UTR_variant, NMD_transcript_variant	30/32	5

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152142 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

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: 0.0000488 AC: 12 AN: 245856 Hom.: 0 AF XY: 0.0000525 AC XY: 7 AN XY: 133402

Gnomad AFR exome AF: 0.0000641

Gnomad AMR exome AF: 0.0000879

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000385

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000911 AC: 133 AN: 1460166 Hom.: 0 Cov.: 31 AF XY: 0.0000978 AC XY: 71 AN XY: 726216

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00298

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152258 Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4 AN XY: 74440

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000244 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	research	PXE International	Mar 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jun 19, 2023	- -

not provided Pathogenic:1 Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1357 of the ABCC6 protein (p.Arg1357Trp). This variant is present in population databases (rs63750428, gnomAD 0.03%). This missense change has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 15645653, 16086317, 28912966). 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: 143119). 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. -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.6	D;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.94		Loss of methylation at R1357 (P = 0.0603);.;
MVP		0.91
MPC		0.42
ClinPred		0.56	D
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs63750428; hg19: chr16-16248624;