16-16155022-C-T

Position:

chr16-16155022-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM5PP5BP4BS2_Supporting

The NM_001171.6(ABCC6):c.3892G>A(p.Val1298Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,556,550 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1298F) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.16

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 3 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001171.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-16155022-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 6578.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 16-16155022-C-T is Pathogenic according to our data. Variant chr16-16155022-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 930520.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.21009487). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR,Digenic geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCC6	NM_001171.6 linkuse as main transcript	c.3892G>A	p.Val1298Ile	missense_variant	28/31	ENST00000205557.12
ABCC6	NM_001351800.1 linkuse as main transcript	c.3550G>A	p.Val1184Ile	missense_variant	28/31
ABCC6	NR_147784.1 linkuse as main transcript	n.3554G>A		non_coding_transcript_exon_variant	26/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.3892G>A	p.Val1298Ile	missense_variant	28/31	1	NM_001171.6	P1	O95255-1
ABCC6	ENST00000576204.6 linkuse as main transcript	n.755G>A		non_coding_transcript_exon_variant	1/2	5
ABCC6	ENST00000456970.6 linkuse as main transcript	c.*901G>A		3_prime_UTR_variant, NMD_transcript_variant	26/29	2			O95255-3
ABCC6	ENST00000622290.5 linkuse as main transcript	c.*64G>A		3_prime_UTR_variant, NMD_transcript_variant	29/32	5

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000138

AC:

AN:

159412

Hom.:

AF XY:

0.000129

AC XY:

AN XY:

84980

show subpopulations

Gnomad AFR exome

AF:

0.000868

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000859

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000160

Gnomad OTH exome

AF:

0.000446

GnomAD4 exome

AF:

0.000256

AC:

359

AN:

1404280

Hom.:

Cov.:

AF XY:

0.000241

AC XY:

167

AN XY:

693408

show subpopulations

Gnomad4 AFR exome

AF:

0.000532

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000276

Gnomad4 SAS exome

AF:

0.0000627

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000292

Gnomad4 OTH exome

AF:

0.000326

GnomAD4 genome

AF:

0.000276

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000673

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:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000242

Hom.:

Bravo

AF:

0.000268

ExAC

AF:

0.000113

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arterial calcification, generalized, of infancy, 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Aug 23, 2019

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM5,PM1,PP2,PP3,PM2. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2022

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1298 of the ABCC6 protein (p.Val1298Ile). This variant is present in population databases (rs63751325, gnomAD 0.1%). This missense change has been observed in individual(s) with vascular anomalies (PMID: 28655553). ClinVar contains an entry for this variant (Variation ID: 930520). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.068

MetaRNN

Benign

0.21

T;T

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

0.84

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.86

N;.

REVEL

Uncertain

0.59

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.051

T;.

Polyphen

1.0

D;.

Vest4

0.50

MVP

0.85

MPC

0.31

ClinPred

0.11

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.49

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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