rs72653760

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

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. 13/22 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:3U:4

Conservation

PhyloP100: 0.921

Publications

10 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

ABCC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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 VariationId is 433220.

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 rank	MANE	Protein	UniProt
ABCC6	NM_001171.6 link	c.1108A>G	p.Asn370Asp	missense_variant	Exon 9 of 31	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12 link	c.1108A>G	p.Asn370Asp	missense_variant	Exon 9 of 31	1	NM_001171.6	ENSP00000205557.7

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

GnomAD2 exomes

AF:

0.000319

AC:

AN:

251166

AF XY:

0.000354

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 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

African (AFR)

AF:

0.0000896

AC:

AN:

33472

American (AMR)

AF:

0.000224

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000651

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000290

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000316

AC:

351

AN:

1111842

Other (OTH)

AF:

0.000265

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000296

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68042

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000416

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:3Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCC6: PM3:Very Strong, PM2, BP4 -

Nov 11, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Autosomal recessive inherited pseudoxanthoma elasticum

Uncertain:2

Mar 01, 2021

PXE International

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCC6-related disorder

Pathogenic:1

Jul 27, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2

Pathogenic:1

May 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arterial calcification, generalized, of infancy, 2

Uncertain:1

Oct 22, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

(source)

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

PhyloP100

0.92

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

Mutation Taster

=35/65

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over