16-16154898-C-T

Position:

chr16-16154898-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_001171.6(ABCC6):c.4016G>A(p.Arg1339His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,611,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1339C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.89

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:

ABCC6 (HGNC:):

ABCC6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 5) in uniprot entity MRP6_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001171.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-16154899-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 16-16154898-C-T is Pathogenic according to our data. Variant chr16-16154898-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16154898-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ABCC6	NM_001171.6 linkuse as main transcript	c.4016G>A	p.Arg1339His	missense_variant	28/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 linkuse as main transcript	c.3674G>A	p.Arg1225His	missense_variant	28/31		NP_001338729.1
ABCC6	NR_147784.1 linkuse as main transcript	n.3678G>A		non_coding_transcript_exon_variant	26/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.4016G>A	p.Arg1339His	missense_variant	28/31	1	NM_001171.6	ENSP00000205557.7		O95255-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

243772

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132246

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000552

Gnomad SAS exome

AF:

0.0000334

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1459846

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726080

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000855

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2016	The R1339H variant in the ABCC6 gene has been reported at least seven times previously in association with PXE (Miksch et al., 2005, Pfendner et al. 2007, Vanakker et al., 2008). The R1339H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1339H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species In silico analysis predicts this variant is probably damaging to the protein structure/function as it occurs in the highly conserved second ATP binding domain required for proper gene function and in which numerous pathogenic variants are clustered. Missense variants at the same residue (R1339C, R1339L) and in nearby residues (L1335P, L1335Q, I1342T) have been reported in the Human Gene Mutation Database in association with PXE (Stenson et al., 2014), supporting the functional importance of this region of the protein. According to the ACMG Guidelines this variant is classified as likely pathogenic; however, the unlikely possibility that it is benign cannot be excluded. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1339 of the ABCC6 protein (p.Arg1339His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 16086317, 18157818). This variant is also known as p.R1339Q. ClinVar contains an entry for this variant (Variation ID: 265021). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC6 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1339 amino acid residue in ABCC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16086317, 19339160, 27994049). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

PXE International

Mar 01, 2021

- -

Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-4.3

D;.

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.98

Loss of methylation at R1339 (P = 0.0308);.;

MVP

0.95

MPC

0.45

ClinPred

0.99

GERP RS

4.8

Varity_R

0.91

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over