rs72653703

Positions:

• chr16-16177518-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001171.6(ABCC6):​c.2524C>T​(p.Gln842*) variant causes a stop gained 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 Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ABCC6 NM_001171.6 stop_gained
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.543

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]

ABCC6 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-16177518-G-A is Pathogenic according to our data. Variant chr16-16177518-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433282.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-16177518-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.2524C>T	p.Gln842*	stop_gained	19/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.2182C>T	p.Gln728*	stop_gained	19/31		NP_001338729.1
ABCC6	NR_147784.1	n.2452+1280C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.2524C>T	p.Gln842*	stop_gained	19/31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000576683.1	n.4C>T		non_coding_transcript_exon_variant	1/3	3
ABCC6	ENST00000622290.5	n.2524C>T		non_coding_transcript_exon_variant	19/32	5		ENSP00000483331.2
ABCC6	ENST00000456970.6	n.2415+1280C>T		intron_variant		2		ENSP00000405002.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

PXE International

Mar 02, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.054
FATHMM_MKL	Benign	0.32	N
Vest4		0.69
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs72653703; hg19: chr16-16271375;