rs72664231

Positions:

• chr16-16163153-CCAA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_001171.6(ABCC6):​c.3343_3345del​(p.Leu1115del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC6 NM_001171.6 inframe_deletion
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.45

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 6 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 70) in uniprot entity MRP6_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001171.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 16-16163153-CCAA-C is Pathogenic according to our data. Variant chr16-16163153-CCAA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433309.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-16163153-CCAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.3343_3345del	p.Leu1115del	inframe_deletion	24/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.3001_3003del	p.Leu1001del	inframe_deletion	24/31		NP_001338729.1
ABCC6	NR_147784.1	n.3169-1592_3169-1590del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.3343_3345del	p.Leu1115del	inframe_deletion	24/31	1	NM_001171.6	ENSP00000205557	P1
ABCC6	ENST00000456970.6	c.*516-1592_*516-1590del		intron_variant, NMD_transcript_variant		2		ENSP00000405002
ABCC6	ENST00000622290.5	c.3343_3345del	p.Leu1115del	inframe_deletion, NMD_transcript_variant	24/32	5		ENSP00000483331

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs72664231; hg19: chr16-16257010;