rs63750273

Positions:

chr16-16157810-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_001171.6(ABCC6):c.3736-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000162 in 1,609,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

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

Conservation

PhyloP100: 6.96

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 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.032358155 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.4, offset of 1, new splice context is: gtttcccctcctgctccaAGctc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP5

Variant 16-16157810-C-T is Pathogenic according to our data. Variant chr16-16157810-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16157810-C-T is described in Lovd as [Pathogenic]. Variant chr16-16157810-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
ABCC6	NM_001171.6 linkuse as main transcript	c.3736-1G>A	splice_acceptor_variant	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 linkuse as main transcript	c.3394-1G>A	splice_acceptor_variant		NP_001338729.1
ABCC6	NR_147784.1 linkuse as main transcript	n.3398-1G>A	splice_acceptor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.3736-1G>A	splice_acceptor_variant	1	NM_001171.6	ENSP00000205557	P1	O95255-1
ABCC6	ENST00000456970.6 linkuse as main transcript	c.*745-1G>A	splice_acceptor_variant, NMD_transcript_variant	2		ENSP00000405002		O95255-3
ABCC6	ENST00000622290.5 linkuse as main transcript	c.3736-1G>A	splice_acceptor_variant, NMD_transcript_variant	5		ENSP00000483331

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000407

AC:

AN:

245914

Hom.:

AF XY:

0.0000374

AC XY:

AN XY:

133612

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000802

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1457688

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

725234

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000522

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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	May 16, 2022	_x000D_Index is not affected, no second variant was found in ABCC6 Criteria applied: PVS1, PM3_STR, PM2_SUP -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 13, 2012	- -
Pathogenic, no assertion criteria provided	research	PXE International	Mar 12, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change affects an acceptor splice site in intron 26 of the ABCC6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ABCC6 are known to be pathogenic (PMID: 11536079, 17617515). This variant is present in population databases (rs63750273, gnomAD 0.009%). Disruption of this splice site has been observed in individual(s) with clinical features of ABCC6-related conditions (PMID: 10811882, 22209248, 24008425, 28655553). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6574). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 27, 2022	- -

Arterial calcification, generalized, of infancy, 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 13, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

GERP RS

5.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.90

Position offset: -2

DS_AL_spliceai

0.99

Position offset: -1

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