NM_001171.6:c.2248-2_2248-1delAG

Variant summary

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

The NM_001171.6(ABCC6):​c.2248-2_2248-1delAG variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,144 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.80
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]

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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 0.03723404 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.3, offset of -35, new splice context is: accccagtttcaccctgtAGatg. 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 16-16178965-CCT-C is Pathogenic according to our data. Variant chr16-16178965-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 433411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16178965-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCC6NM_001171.6 linkc.2248-2_2248-1delAG splice_acceptor_variant, intron_variant Intron 17 of 30 ENST00000205557.12 NP_001162.5
ABCC6NM_001351800.1 linkc.1906-2_1906-1delAG splice_acceptor_variant, intron_variant Intron 17 of 30 NP_001338729.1
ABCC6NR_147784.1 linkn.2285-2_2285-1delAG splice_acceptor_variant, intron_variant Intron 17 of 28

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCC6ENST00000205557.12 linkc.2248-2_2248-1delAG splice_acceptor_variant, intron_variant Intron 17 of 30 1 NM_001171.6 ENSP00000205557.7 O95255-1
ABCC6ENST00000456970.6 linkn.2248-2_2248-1delAG splice_acceptor_variant, intron_variant Intron 17 of 28 2 ENSP00000405002.2 O95255-3
ABCC6ENST00000622290.5 linkn.2248-2_2248-1delAG splice_acceptor_variant, intron_variant Intron 17 of 31 5 ENSP00000483331.2 A0A8C8Q0G8

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152214
Hom.:
0
Cov.:
33
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000890
AC:
13
AN:
1459930
Hom.:
0
AF XY:
0.00000826
AC XY:
6
AN XY:
726274
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:
0.0000117
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74356
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:2
Sep 22, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 02, 2021
PXE International
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Pseudoxanthoma elasticum, forme fruste Pathogenic:1
-
Centogene AG - the Rare Disease Company
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 Pathogenic:1
Apr 14, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.70
Position offset: -24
DS_AL_spliceai
1.0
Position offset: 0

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.

Other links and lift over

dbSNP: rs111113624; hg19: chr16-16272822; API