rs63749796

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_001171.6(ABCC6):​c.3712G>T​(p.Asp1238Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1238H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

9
7
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.77

Publications

1 publications found
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 Gene-Disease associations (from GenCC):
  • arterial calcification, generalized, of infancy, 2
    Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
  • autosomal recessive inherited pseudoxanthoma elasticum
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P
  • arterial calcification of infancy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain 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 chr16-16159505-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6581.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCC6NM_001171.6 linkc.3712G>T p.Asp1238Tyr missense_variant Exon 26 of 31 ENST00000205557.12 NP_001162.5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCC6ENST00000205557.12 linkc.3712G>T p.Asp1238Tyr missense_variant Exon 26 of 31 1 NM_001171.6 ENSP00000205557.7 O95255-1
ABCC6ENST00000456970.6 linkn.*721G>T non_coding_transcript_exon_variant Exon 24 of 29 2 ENSP00000405002.2 O95255-3
ABCC6ENST00000622290.5 linkn.3712G>T non_coding_transcript_exon_variant Exon 26 of 32 5 ENSP00000483331.2 A0A8C8Q0G8
ABCC6ENST00000456970.6 linkn.*721G>T 3_prime_UTR_variant Exon 24 of 29 2 ENSP00000405002.2 O95255-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461852
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727236
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112000
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.54
D;.
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Pathogenic
0.47
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Benign
0.21
N;.
PhyloP100
7.8
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-5.3
D;.
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;.
Vest4
0.76
MutPred
0.61
Loss of phosphorylation at Y1239 (P = 0.0912);.;
MVP
0.93
MPC
0.38
ClinPred
1.0
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.54
gMVP
0.75
Mutation Taster
=26/74
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs63749796; hg19: chr16-16253362; API