16-16165741-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_001171.6(ABCC6):​c.3188T>C​(p.Leu1063Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1063R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

ABCC6
NM_001171.6 missense

Scores

13
4
2

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 5.88
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.

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
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-16165741-A-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCC6NM_001171.6 linkc.3188T>C p.Leu1063Pro missense_variant Exon 23 of 31 ENST00000205557.12 NP_001162.5
ABCC6NM_001351800.1 linkc.2846T>C p.Leu949Pro missense_variant Exon 23 of 31 NP_001338729.1
ABCC6NR_147784.1 linkn.3050T>C non_coding_transcript_exon_variant Exon 22 of 29

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCC6ENST00000205557.12 linkc.3188T>C p.Leu1063Pro missense_variant Exon 23 of 31 1 NM_001171.6 ENSP00000205557.7 O95255-1
ABCC6ENST00000456970.6 linkn.*397T>C non_coding_transcript_exon_variant Exon 22 of 29 2 ENSP00000405002.2 O95255-3
ABCC6ENST00000622290.5 linkn.3188T>C non_coding_transcript_exon_variant Exon 23 of 32 5 ENSP00000483331.2 A0A8C8Q0G8
ABCC6ENST00000456970.6 linkn.*397T>C 3_prime_UTR_variant Exon 22 of 29 2 ENSP00000405002.2 O95255-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1
Feb 16, 2021
PXE International
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.79
D;.
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.81
T;T
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Pathogenic
3.3
M;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Pathogenic
-4.7
D;.
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.0050
D;.
Polyphen
1.0
D;.
Vest4
0.97
MutPred
0.90
Gain of disorder (P = 0.0185);.;
MVP
0.97
MPC
0.47
ClinPred
0.99
D
GERP RS
5.4
Varity_R
0.96
gMVP
0.81

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.

Other links and lift over

dbSNP: rs72657695; hg19: chr16-16259598; API