rs72653760

Positions:

chr16-16202069-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP5BP4

The NM_001171.6(ABCC6):c.1108A>G(p.Asn370Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 0.921

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a transmembrane_region Helical; Name=7 (size 20) in uniprot entity MRP6_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001171.6

PP5

Variant 16-16202069-T-C is Pathogenic according to our data. Variant chr16-16202069-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 433220.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr16-16202069-T-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.13671193). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ABCC6	NM_001171.6 linkuse as main transcript	c.1108A>G	p.Asn370Asp	missense_variant	9/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 linkuse as main transcript	c.766A>G	p.Asn256Asp	missense_variant	9/31		NP_001338729.1
ABCC6	NR_147784.1 linkuse as main transcript	n.1145A>G		non_coding_transcript_exon_variant	9/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.1108A>G	p.Asn370Asp	missense_variant	9/31	1	NM_001171.6	ENSP00000205557	P1	O95255-1

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000319

AC:

AN:

251166

Hom.:

AF XY:

0.000354

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000441

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000289

AC:

422

AN:

1461668

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

211

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.000651

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000316

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000296

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000523

Hom.:

Bravo

AF:

0.000366

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

ABCC6-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 27, 2023

The ABCC6 c.1108A>G variant is predicted to result in the amino acid substitution p.Asn370Asp. This variant has been reported in the compound heterozygous state in multiple individuals with pseudoxanthoma elasticum. In at least three patients, the second variant affecting the ABCC6 gene was the c.3421C>T (p.Arg1141Ter) recurrent pathogenic variant (Miksch et al. 2005. PubMed ID: 16086317, Saeidian et al. 2021. PubMed ID: 34906475). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-16295926-T-C). This variant is interpreted as likely pathogenic. -

Autosomal recessive inherited pseudoxanthoma elasticum

Uncertain:1

Uncertain significance, no assertion criteria provided

research

PXE International

Mar 01, 2021

- -

Arterial calcification, generalized, of infancy, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 22, 2018

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP5,BP4. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 11, 2016

The p.Asn370Asp variant in ABCC6 has been reported in 2 compound heterozygous individuals with Pseudoxanthoma elasticum (Miksch 2005). This variant has been identified in 0.038% (25/66650) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72653760). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. However, computational prediction tools do not provide strong support for an impact to the protein and the amino acid position is poorly conserved reducing confidence in a pathogenic interpretation. In summary, additional studies are required to establish the clinical significance of the p.Asn370Asp variant given limited cases studies and conflicting computational and conservation assessments. It should also be noted that this variant occurs in a region of the gene that has high homology to a pseudogene. Caution should be exercised in the analytical detection of the variant in patient DNA. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.7

N;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.0070

D;.

Sift4G

Uncertain

0.0070

D;T

Polyphen

0.14

B;.

Vest4

0.72

MVP

0.65

MPC

0.080

ClinPred

0.023

GERP RS

-3.0

Varity_R

0.23

gMVP

0.56

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.

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