rs8058696

Positions:

• chr16-16185012-G-C
• chr16-16185012-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001171.6(ABCC6):​c.1890C>G​(p.Thr630=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,608,362 control chromosomes in the GnomAD database, including 178,860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14341 hom., cov: 31)
  • Exomes 𝑓: 0.47 (164519 hom.)
• Consequence: ABCC6 NM_001171.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.551

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-16185012-G-C is Benign according to our data. Variant chr16-16185012-G-C is described in ClinVar as [Benign]. Clinvar id is 433246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16185012-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.551 with no splicing effect.
• 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.1890C>G	p.Thr630=	synonymous_variant	15/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.1548C>G	p.Thr516=	synonymous_variant	15/31
ABCC6	NR_147784.1	n.1927C>G		non_coding_transcript_exon_variant	15/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.1890C>G	p.Thr630=	synonymous_variant	15/31	1	NM_001171.6	P1
ABCC6	ENST00000622290.5	c.1890C>G	p.Thr630=	synonymous_variant, NMD_transcript_variant	15/32	5
ABCC6	ENST00000456970.6	c.1890C>G	p.Thr630=	synonymous_variant, NMD_transcript_variant	15/29	2

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64710 AN: 151562 Hom.: 14340 Cov.: 31

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.424

GnomAD3 exomes AF: 0.419 AC: 105062 AN: 251026 Hom.: 23399 AF XY: 0.412 AC XY: 55956 AN XY: 135706

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: 0.446

Gnomad NFE exome AF: 0.490

Gnomad OTH exome AF: 0.444

GnomAD4 exome AF: 0.468 AC: 681196 AN: 1456680 Hom.: 164519 Cov.: 49 AF XY: 0.461 AC XY: 334274 AN XY: 724862

Gnomad4 AFR exome AF: 0.349

Gnomad4 AMR exome AF: 0.467

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: 64721 AN: 151682 Hom.: 14341 Cov.: 31 AF XY: 0.417 AC XY: 30889 AN XY: 74126

Gnomad4 AFR AF: 0.353

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.425

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.436

Gnomad4 NFE AF: 0.499

Gnomad4 OTH AF: 0.419

Alfa AF: 0.459 Hom.: 11900

Bravo AF: 0.428

Asia WGS AF: 0.210 AC: 730 AN: 3478

EpiCase AF: 0.483

EpiControl AF: 0.478

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

not provided Benign:2

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

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.12
DANN	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs8058696; hg19: chr16-16278869; COSMIC: COSV52741428;