rs58694313

chr16-16157674-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001171.6(ABCC6):c.3871G>A(p.Ala1291Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00496 in 1,614,016 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (162 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (154 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.269

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001171.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025525987).
• BP6: Variant 16-16157674-C-T is Benign according to our data. Variant chr16-16157674-C-T is described in ClinVar as [Benign]. Clinvar id is 379215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16157674-C-T is described in Lovd as [Pathogenic]. Variant chr16-16157674-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.3871G>A	p.Ala1291Thr	missense_variant	27/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.3529G>A	p.Ala1177Thr	missense_variant	27/31
ABCC6	NR_147784.1	n.3533G>A		non_coding_transcript_exon_variant	25/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.3871G>A	p.Ala1291Thr	missense_variant	27/31	1	NM_001171.6	P1
ABCC6	ENST00000622290.5	c.3871G>A	p.Ala1291Thr	missense_variant, NMD_transcript_variant	27/32	5
ABCC6	ENST00000456970.6	c.*880G>A		3_prime_UTR_variant, NMD_transcript_variant	25/29	2

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3926 AN: 152042 Hom.: 159 Cov.: 31

Gnomad AFR AF: 0.0892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0197

GnomAD3 exomes AF: 0.00693 AC: 1739 AN: 251118 Hom.: 73 AF XY: 0.00506 AC XY: 687 AN XY: 135798

Gnomad AFR exome AF: 0.0928

Gnomad AMR exome AF: 0.00469

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00277 AC: 4049 AN: 1461856 Hom.: 154 Cov.: 32 AF XY: 0.00247 AC XY: 1797 AN XY: 727236

Gnomad4 AFR exome AF: 0.0940

Gnomad4 AMR exome AF: 0.00512

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000187

Gnomad4 OTH exome AF: 0.00646

GnomAD4 genome AF: 0.0260 AC: 3955 AN: 152160 Hom.: 162 Cov.: 31 AF XY: 0.0251 AC XY: 1864 AN XY: 74404

Gnomad4 AFR AF: 0.0897

Gnomad4 AMR AF: 0.00995

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00564 Hom.: 51

Bravo AF: 0.0301

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0883 AC: 388

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00884 AC: 1073

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, no assertion criteria provided	research	PXE International	Mar 01, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Arterial calcification, generalized, of infancy, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Pseudoxanthoma elasticum, forme fruste Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.15	N
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.22
Sift	Uncertain	0.026	D;.
Sift4G	Benign	0.067	T;.
Polyphen		0.21	B;.
Vest4		0.19
MVP		0.72
MPC		0.073
ClinPred		0.011	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
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

Other links and lift over

dbSNP: rs58694313; hg19: chr16-16251531;