16-16190259-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001171.6(ABCC6):c.1540G>A(p.Val514Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000693 in 1,614,144 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00055 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00071 ( 6 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 1.65

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 Benign. Variant got -11 ACMG points.

PM1

In a domain ABC transmembrane type-1 1 (size 282) in uniprot entity MRP6_HUMAN there are 31 pathogenic changes around while only 9 benign (78%) in NM_001171.6

BP4

Computational evidence support a benign effect (MetaRNN=0.012797385).

BP6

Variant 16-16190259-C-T is Benign according to our data. Variant chr16-16190259-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 433236.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=5}. Variant chr16-16190259-C-T is described in Lovd as [Benign]. Variant chr16-16190259-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000709 (1036/1461880) while in subpopulation MID AF= 0.0102 (59/5768). AF 95% confidence interval is 0.00814. There are 6 homozygotes in gnomad4_exome. There are 580 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ABCC6	NM_001171.6 link	c.1540G>A	p.Val514Ile	missense_variant	Exon 12 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 link	c.1198G>A	p.Val400Ile	missense_variant	Exon 12 of 31		NP_001338729.1
ABCC6	NR_147784.1 link	n.1577G>A		non_coding_transcript_exon_variant	Exon 12 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCC6	ENST00000205557.12 link	c.1540G>A	p.Val514Ile	missense_variant	Exon 12 of 31	1	NM_001171.6	ENSP00000205557.7	O95255-1
ABCC6	ENST00000456970.6 link	n.1540G>A		non_coding_transcript_exon_variant	Exon 12 of 29	2		ENSP00000405002.2	O95255-3
ABCC6	ENST00000622290.5 link	n.1540G>A		non_coding_transcript_exon_variant	Exon 12 of 32	5		ENSP00000483331.2	A0A8C8Q0G8

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00106

AC:

267

AN:

251330

Hom.:

AF XY:

0.00118

AC XY:

160

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00310

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000607

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000709

AC:

1036

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000798

AC XY:

580

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00163

Gnomad4 ASJ exome

AF:

0.00249

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00328

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000425

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.000545

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000870

Hom.:

Bravo

AF:

0.000688

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000980

AC:

119

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2025	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 29, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2025	ABCC6: BP4, BS2 -

ABCC6-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2022

The ABCC6 c.1540G>A variant is predicted to result in the amino acid substitution p.Val514Ile. This variant has been previously reported in the heterozygous state in an individual with vascular anomalies (Mattassi et al. 2018. PubMed ID: 28655553). This variant has also been identified as a polymorphism in a family with pseudoxanthoma elasticum (Table 2, Miksch. 2005. PubMed ID: 16086317), and it was recently reassessed as likely benign (Verschuere et al. 2021. PubMed ID: 32873932, Supplementary Tables). This variant is reported in 0.31% of alleles in individuals of South Asian descent in gnomAD, including three homozygotes (http://gnomad.broadinstitute.org/variant/16-16284116-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 12, 2024

Variant summary: ABCC6 c.1540G>A (p.Val514Ile) results in a conservative amino acid change located in the first transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 1607170 control chromosomes, predominantly at a frequency of 0.0032 within the South Asian subpopulation in the gnomAD database (v4.1 dataset), including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in ABCC6 causing Pseudoxanthoma Elasticum phenotype. To our knowledge, no occurrence of c.1540G>A in individuals affected with Pseudoxanthoma Elasticum and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 433236). Based on the evidence outlined above, the variant was classified as likely benign. -

Autosomal recessive inherited pseudoxanthoma elasticum

Benign:1

Likely benign, no assertion criteria provided

research

PXE International

Feb 02, 2021

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.63

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.63

N;.

REVEL

Benign

0.16

Sift

Benign

0.18

T;.

Sift4G

Benign

0.29

T;T

Polyphen

0.17

B;.

Vest4

0.15

MVP

0.55

MPC

0.065

ClinPred

0.0075

GERP RS

0.16

Varity_R

0.053

gMVP

0.52

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