rs72664233

Positions:

chr16-16157769-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001171.6(ABCC6):c.3775del(p.Trp1259GlyfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,486 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.07

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 16-16157769-CA-C is Pathogenic according to our data. Variant chr16-16157769-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 6563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16157769-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCC6	NM_001171.6 linkuse as main transcript	c.3775del	p.Trp1259GlyfsTer14	frameshift_variant	27/31	ENST00000205557.12
ABCC6	NM_001351800.1 linkuse as main transcript	c.3433del	p.Trp1145GlyfsTer14	frameshift_variant	27/31
ABCC6	NR_147784.1 linkuse as main transcript	n.3437del		non_coding_transcript_exon_variant	25/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.3775del	p.Trp1259GlyfsTer14	frameshift_variant	27/31	1	NM_001171.6	P1	O95255-1
ABCC6	ENST00000622290.5 linkuse as main transcript	c.3775del	p.Trp1259GlyfsTer14	frameshift_variant, NMD_transcript_variant	27/32	5
ABCC6	ENST00000456970.6 linkuse as main transcript	c.*784del		3_prime_UTR_variant, NMD_transcript_variant	25/29	2			O95255-3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000839

AC:

AN:

250336

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135538

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000159

AC:

233

AN:

1461404

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

132

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000206

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, no assertion criteria provided	research	PXE International	Mar 01, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2009	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Trp1259Glyfs*14) 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 (rs72664233, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 10835643). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6563). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2020	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19904211, 19339160, 10835642, 10835643, 29800625, 15727254, 11536079, 16835894, 16086317) -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over