rs63750874

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate

The NM_001171.6(ABCC6):c.4501G>T(p.Gly1501Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,612,538 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. G1501S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.64

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 283) in uniprot entity MRP6_HUMAN there are 90 pathogenic changes around while only 13 benign (87%) in NM_001171.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-16150144-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433368.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCC6	NM_001171.6 linkuse as main transcript	c.4501G>T	p.Gly1501Cys	missense_variant	31/31	ENST00000205557.12
ABCC6	NM_001351800.1 linkuse as main transcript	c.4159G>T	p.Gly1387Cys	missense_variant	31/31
ABCC6	NR_147784.1 linkuse as main transcript	n.4163G>T		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.4501G>T	p.Gly1501Cys	missense_variant	31/31	1	NM_001171.6	P1	O95255-1
ABCC6	ENST00000456970.6 linkuse as main transcript	c.*1510G>T		3_prime_UTR_variant, NMD_transcript_variant	29/29	2			O95255-3
ABCC6	ENST00000622290.5 linkuse as main transcript	c.*673G>T		3_prime_UTR_variant, NMD_transcript_variant	32/32	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249730

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135434

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460330

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726442

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:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.31

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

T;T

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.3

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-7.6

D;.

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.55

MutPred

0.70

Loss of disorder (P = 0.0222);.;

MVP

0.93

MPC

0.42

ClinPred

0.99

GERP RS

3.9

Varity_R

0.89

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over