rs72664218

Variant names:

• chr16-16187133-A-AG
• rs72664218
• NM_001171.6:c.1857dupC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001171.6(ABCC6):​c.1857dupC​(p.Ser620LeufsTer121) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ABCC6 NM_001171.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.127
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• arterial calcification, generalized, of infancy, 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• autosomal recessive inherited pseudoxanthoma elasticum

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• arterial calcification of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 16-16187133-A-AG is Pathogenic according to our data. Variant chr16-16187133-A-AG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 433245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	NM_001171.6	MANE Select	c.1857dupC	p.Ser620LeufsTer121	frameshift	Exon 14 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.1857dupC	p.Ser620LeufsTer121	frameshift	Exon 14 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.1857dupC	p.Ser620LeufsTer121	frameshift	Exon 14 of 30	NP_001427239.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.1857dupC	p.Ser620LeufsTer121	frameshift	Exon 14 of 31	ENSP00000205557.7
	ABCC6	ENST00000456970.6	TSL:2	n.1857dupC		non_coding_transcript_exon	Exon 14 of 29	ENSP00000405002.2
	ABCC6	ENST00000622290.5	TSL:5	n.1857dupC		non_coding_transcript_exon	Exon 14 of 32	ENSP00000483331.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460780 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726714

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111288

Other (OTH) AF: 0.0000166 AC: 1 AN: 60336

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1

Mar 02, 2021

PXE International

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

not provided Pathogenic:1

Aug 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser620Leufs*121) in the ABCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC6 are known to be pathogenic (PMID: 11536079, 17617515). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 17617515, 34205333, 34906475). ClinVar contains an entry for this variant (Variation ID: 433245). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
Mutation Taster		=6/194	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs72664218; hg19: chr16-16280990;