16-16178919-C-T

Position:

chr16-16178919-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.2294G>A(p.Arg765Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,613,428 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R765G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.08

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001171.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-16178919-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1520297.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 16-16178919-C-T is Pathogenic according to our data. Variant chr16-16178919-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16178919-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCC6	NM_001171.6 linkuse as main transcript	c.2294G>A	p.Arg765Gln	missense_variant	18/31	ENST00000205557.12
ABCC6	NM_001351800.1 linkuse as main transcript	c.1952G>A	p.Arg651Gln	missense_variant	18/31
ABCC6	NR_147784.1 linkuse as main transcript	n.2331G>A		non_coding_transcript_exon_variant	18/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.2294G>A	p.Arg765Gln	missense_variant	18/31	1	NM_001171.6	P1	O95255-1
ABCC6	ENST00000622290.5 linkuse as main transcript	c.2294G>A	p.Arg765Gln	missense_variant, NMD_transcript_variant	18/32	5
ABCC6	ENST00000456970.6 linkuse as main transcript	c.2294G>A	p.Arg765Gln	missense_variant, NMD_transcript_variant	18/29	2			O95255-3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250548

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461244

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726930

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 29, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 765 of the ABCC6 protein (p.Arg765Gln). This variant is present in population databases (rs67561842, gnomAD 0.02%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 12673275, 30805891). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30337). 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%. Experimental studies have shown that this missense change affects ABCC6 function (PMID: 30154241). This variant disrupts the p.Arg765 amino acid residue in ABCC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18157818; Invitae). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	PXE International	Mar 01, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -

Arterial calcification, generalized, of infancy, 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.5

D;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;.

Vest4

0.73

MutPred

0.99

Loss of MoRF binding (P = 0.0196);Loss of MoRF binding (P = 0.0196);

MVP

0.96

MPC

0.43

ClinPred

0.84

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.87

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