rs767359198

Positions:

chr16-16169774-CAGAGGA-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong

The NM_001171.6(ABCC6):c.2861_2866del(p.Phe954_Leu955del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000144 in 1,593,594 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U:1

Conservation

PhyloP100: 5.92

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.

PM1

In a domain ABC transmembrane type-1 2 (size 281) in uniprot entity MRP6_HUMAN there are 30 pathogenic changes around while only 5 benign (86%) in NM_001171.6

PP5

Variant 16-16169774-CAGAGGA-C is Pathogenic according to our data. Variant chr16-16169774-CAGAGGA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ABCC6	NM_001171.6 linkuse as main transcript	c.2861_2866del	p.Phe954_Leu955del	inframe_deletion	22/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 linkuse as main transcript	c.2519_2524del	p.Phe840_Leu841del	inframe_deletion	22/31		NP_001338729.1
ABCC6	NR_147784.1 linkuse as main transcript	n.2723_2728del		non_coding_transcript_exon_variant	21/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.2861_2866del	p.Phe954_Leu955del	inframe_deletion	22/31	1	NM_001171.6	ENSP00000205557	P1	O95255-1
ABCC6	ENST00000456970.6 linkuse as main transcript	c.70_75del		3_prime_UTR_variant, NMD_transcript_variant	21/29	2		ENSP00000405002		O95255-3
ABCC6	ENST00000622290.5 linkuse as main transcript	c.2861_2866del	p.Phe954_Leu955del	inframe_deletion, NMD_transcript_variant	22/32	5		ENSP00000483331

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000333

AC:

AN:

210238

Hom.:

AF XY:

0.0000263

AC XY:

AN XY:

113962

show subpopulations

Gnomad AFR exome

AF:

0.000312

Gnomad AMR exome

AF:

0.0000997

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000763

AC:

AN:

1441380

Hom.:

AF XY:

0.00000839

AC XY:

AN XY:

715286

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.0000728

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000240

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.07e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000147

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2018	The c.2861_2866delTCCTCT variant has been published previously in three patients who were also heterozygous for the R518Q variant in the ABCC6 gene (Hosen et al., 2015). It was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This deletion causes the loss of two conserved residues, Phenylalanine 954 and Leucine 955, in a conserved transmembrane domain. In summary, the c.2861_2866delTCCTCT variant is a strong candidate for a disease-causing variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 22, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 265019). This variant has been observed in individual(s) with pseudoxanthoma elasticum or generalized arterial calcification of infancy (PMID: 25264593, 33005041). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs767359198, gnomAD 0.02%). This variant, c.2861_2866del, results in the deletion of 2 amino acid(s) of the ABCC6 protein (p.Phe954_Leu955del), but otherwise preserves the integrity of the reading frame. -

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

Name

Calibrated prediction

Score

Prediction

Splicing

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