rs72653767

Positions:

• chr16-16192873-A-T

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.1388T>A​(p.Leu463His) variant causes a missense change involving the alteration of a 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L463P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.56

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 domain ABC transmembrane type-1 1 (size 282) in uniprot entity MRP6_HUMAN there are 54 pathogenic changes around while only 20 benign (73%) in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.1388T>A	p.Leu463His	missense_variant	11/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.1046T>A	p.Leu349His	missense_variant	11/31
ABCC6	NR_147784.1	n.1425T>A		non_coding_transcript_exon_variant	11/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.1388T>A	p.Leu463His	missense_variant	11/31	1	NM_001171.6	P1
ABCC6	ENST00000622290.5	c.1388T>A	p.Leu463His	missense_variant, NMD_transcript_variant	11/32	5
ABCC6	ENST00000456970.6	c.1388T>A	p.Leu463His	missense_variant, NMD_transcript_variant	11/29	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1

Uncertain significance, no assertion criteria provided

research

PXE International

Feb 16, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 21, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 433250). This missense change has been observed in individual(s) with ABCC6-related conditions (PMID: 17617515). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 463 of the ABCC6 protein (p.Leu463His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.2	D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.90
MutPred		0.81		Loss of stability (P = 0.0199);Loss of stability (P = 0.0199);
MVP		0.97
MPC		0.43
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.80

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: rs72653767; hg19: chr16-16286730;