rs8058694

Positions:

• chr16-16185006-G-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.1896C>A​(p.His632Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,608,938 control chromosomes in the GnomAD database, including 178,917 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 0.43 (14343 hom., cov: 31)
  • Exomes 𝑓: 0.47 (164574 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.15

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 domain ABC transporter 1 (size 224) in uniprot entity MRP6_HUMAN there are 58 pathogenic changes around while only 9 benign (87%) in NM_001171.6
• BP4: Computational evidence support a benign effect (MetaRNN=2.1311641E-4).
• BP6: Variant 16-16185006-G-T is Benign according to our data. Variant chr16-16185006-G-T is described in ClinVar as [Benign]. Clinvar id is 433247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16185006-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.1896C>A	p.His632Gln	missense_variant	15/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.1554C>A	p.His518Gln	missense_variant	15/31
ABCC6	NR_147784.1	n.1933C>A		non_coding_transcript_exon_variant	15/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.1896C>A	p.His632Gln	missense_variant	15/31	1	NM_001171.6	P1
ABCC6	ENST00000622290.5	c.1896C>A	p.His632Gln	missense_variant, NMD_transcript_variant	15/32	5
ABCC6	ENST00000456970.6	c.1896C>A	p.His632Gln	missense_variant, NMD_transcript_variant	15/29	2

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64716 AN: 151590 Hom.: 14342 Cov.: 31

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.425

GnomAD3 exomes AF: 0.419 AC: 105156 AN: 251100 Hom.: 23455 AF XY: 0.413 AC XY: 56008 AN XY: 135740

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.470

Gnomad ASJ exome AF: 0.426

Gnomad EAS exome AF: 0.159

Gnomad SAS exome AF: 0.261

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.490

Gnomad OTH exome AF: 0.445

GnomAD4 exome AF: 0.468 AC: 681571 AN: 1457230 Hom.: 164574 Cov.: 52 AF XY: 0.461 AC XY: 334447 AN XY: 725092

Gnomad4 AFR exome AF: 0.349

Gnomad4 AMR exome AF: 0.468

Gnomad4 ASJ exome AF: 0.428

Gnomad4 EAS exome AF: 0.186

Gnomad4 SAS exome AF: 0.261

Gnomad4 FIN exome AF: 0.454

Gnomad4 NFE exome AF: 0.501

Gnomad4 OTH exome AF: 0.437

GnomAD4 genome AF: 0.427 AC: 64726 AN: 151708 Hom.: 14343 Cov.: 31 AF XY: 0.417 AC XY: 30888 AN XY: 74128

Gnomad4 AFR AF: 0.354

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.437

Gnomad4 NFE AF: 0.499

Gnomad4 OTH AF: 0.419

Alfa AF: 0.464 Hom.: 22533

Bravo AF: 0.428

TwinsUK AF: 0.495 AC: 1836

ALSPAC AF: 0.492 AC: 1895

ESP6500AA AF: 0.358 AC: 1574

ESP6500EA AF: 0.502 AC: 4313

ExAC AF: 0.415 AC: 50419

Asia WGS AF: 0.211 AC: 731 AN: 3478

EpiCase AF: 0.483

EpiControl AF: 0.479

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	Jul 14, 2021	- -
Benign, criteria provided, single submitter	research	PXE International	Mar 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Pseudoxanthoma elasticum, forme fruste Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.051
DANN	Benign	0.61
DEOGEN2	Benign	0.097	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.27	T;T
MetaRNN	Benign	0.00021	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.62	N;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.72	N;.
REVEL	Uncertain	0.29
Sift	Benign	0.24	T;.
Sift4G	Benign	0.65	T;T
Polyphen		0.0010	B;.
Vest4		0.026
MutPred		0.29		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MPC		0.067
ClinPred		1.0	D
GERP RS		-9.0
Varity_R		0.14
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8058694; hg19: chr16-16278863; COSMIC: COSV52741414;