rs72657689

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_001171.6(ABCC6):​c.2848G>T​(p.Ala950Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. A950T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

3
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.456
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 Likely_pathogenic. Variant got 6 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 chr16-16169793-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCC6NM_001171.6 linkc.2848G>T p.Ala950Ser missense_variant Exon 22 of 31 ENST00000205557.12 NP_001162.5
ABCC6NM_001351800.1 linkc.2506G>T p.Ala836Ser missense_variant Exon 22 of 31 NP_001338729.1
ABCC6NR_147784.1 linkn.2710G>T non_coding_transcript_exon_variant Exon 21 of 29

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCC6ENST00000205557.12 linkc.2848G>T p.Ala950Ser missense_variant Exon 22 of 31 1 NM_001171.6 ENSP00000205557.7 O95255-1
ABCC6ENST00000456970.6 linkn.*57G>T non_coding_transcript_exon_variant Exon 21 of 29 2 ENSP00000405002.2 O95255-3
ABCC6ENST00000622290.5 linkn.2848G>T non_coding_transcript_exon_variant Exon 22 of 32 5 ENSP00000483331.2 A0A8C8Q0G8
ABCC6ENST00000456970.6 linkn.*57G>T 3_prime_UTR_variant Exon 21 of 29 2 ENSP00000405002.2 O95255-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.01e-7
AC:
1
AN:
1427326
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
706934
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000392
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Uncertain
0.049
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
14
DANN
Benign
0.67
DEOGEN2
Benign
0.18
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.25
N
LIST_S2
Benign
0.67
T
M_CAP
Uncertain
0.29
D
MetaRNN
Benign
0.24
T
MetaSVM
Benign
-0.37
T
MutationAssessor
Benign
0.17
N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
0.36
N
REVEL
Uncertain
0.36
Sift
Benign
0.73
T
Sift4G
Benign
0.41
T
Polyphen
0.58
P
Vest4
0.18
MutPred
0.51
Gain of catalytic residue at L946 (P = 0.1377);
MVP
0.49
MPC
0.070
ClinPred
0.17
T
GERP RS
-2.3
Varity_R
0.070
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.41
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.41
Position offset: -24

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-16263650; API