chr16-16163153-CCAA-C

Position:

• 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 ENST00000205557.12(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). Synonymous variant affecting the same amino acid position (i.e. L1115L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC6 ENST00000205557.12 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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000205557.12
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000205557.12. 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;