rs67867306

Positions:

• chr16-16177499-AT-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS2_Supporting

The NM_001171.6(ABCC6):​c.2542del​(p.Met848CysfsTer83) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,614,154 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: ABCC6 NM_001171.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 1.46

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 Pathogenic. Variant got 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-16177499-AT-A is Pathogenic according to our data. Variant chr16-16177499-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16177499-AT-A is described in Lovd as [Pathogenic].
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR,Digenic geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.2542del	p.Met848CysfsTer83	frameshift_variant	19/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.2200del	p.Val734CysfsTer83	frameshift_variant	19/31		NP_001338729.1
ABCC6	NR_147784.1	n.2452+1298del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.2542del	p.Met848CysfsTer83	frameshift_variant	19/31	1	NM_001171.6	ENSP00000205557	P1
ABCC6	ENST00000576683.1	n.22del		non_coding_transcript_exon_variant	1/3	3
ABCC6	ENST00000622290.5	c.2542del	p.Met848CysfsTer83	frameshift_variant, NMD_transcript_variant	19/32	5		ENSP00000483331
ABCC6	ENST00000456970.6	c.2415+1298del		intron_variant, NMD_transcript_variant		2		ENSP00000405002

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 251422 Hom.: 0 AF XY: 0.000213 AC XY: 29 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00288

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000202 AC: 296 AN: 1461856 Hom.: 2 Cov.: 69 AF XY: 0.000193 AC XY: 140 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00730

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00425

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000162

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change creates a premature translational stop signal (p.Val848Cysfs*83) 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 present in population databases (rs67867306, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with pseudoxanthoma elasticum (PMID: 28912966). ClinVar contains an entry for this variant (Variation ID: 433283). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1

Uncertain significance, no assertion criteria provided

research

PXE International

Mar 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs67867306; hg19: chr16-16271356;