rs1555514899

chr16-16190236-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001171.6(ABCC6):c.1563G>C(p.Glu521Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

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 8 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 61) in uniprot entity MRP6_HUMAN there are 14 pathogenic changes around while only 5 benign (74%) in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.1563G>C	p.Glu521Asp	missense_variant	12/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.1221G>C	p.Glu407Asp	missense_variant	12/31
ABCC6	NR_147784.1	n.1600G>C		non_coding_transcript_exon_variant	12/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.1563G>C	p.Glu521Asp	missense_variant	12/31	1	NM_001171.6	P1
ABCC6	ENST00000622290.5	c.1563G>C	p.Glu521Asp	missense_variant, NMD_transcript_variant	12/32	5
ABCC6	ENST00000456970.6	c.1563G>C	p.Glu521Asp	missense_variant, NMD_transcript_variant	12/29	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1

Uncertain significance, criteria provided, single submitter

research

PXE International

Feb 16, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.92		Gain of catalytic residue at E521 (P = 0.1328);Gain of catalytic residue at E521 (P = 0.1328);
MVP		0.95
MPC		0.39
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555514899; hg19: chr16-16284093;