rs58760581

Positions:

• chr16-16154619-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001171.6(ABCC6):​c.4208+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,611,610 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 31)
  • Exomes 𝑓: 0.018 (329 hom.)
• Consequence: ABCC6 NM_001171.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.37

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-16154619-C-T is Benign according to our data. Variant chr16-16154619-C-T is described in ClinVar as [Benign]. Clinvar id is 433396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16154619-C-T is described in Lovd as [Benign]. Variant chr16-16154619-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0122 (1850/152242) while in subpopulation SAS AF= 0.0415 (200/4820). AF 95% confidence interval is 0.0368. There are 18 homozygotes in gnomad4. There are 900 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.4208+9G>A		intron_variant		ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.3866+9G>A		intron_variant			NP_001338729.1
ABCC6	NR_147784.1	n.3870+9G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.4208+9G>A		intron_variant		1	NM_001171.6	ENSP00000205557	P1
ABCC6	ENST00000456970.6	c.*1217+9G>A		intron_variant, NMD_transcript_variant		2		ENSP00000405002
ABCC6	ENST00000622290.5	c.*380+9G>A		intron_variant, NMD_transcript_variant		5		ENSP00000483331

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1849 AN: 152124 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.0415

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0151 AC: 3735 AN: 246964 Hom.: 58 AF XY: 0.0172 AC XY: 2312 AN XY: 134392

Gnomad AFR exome AF: 0.00288

Gnomad AMR exome AF: 0.00539

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.000438

Gnomad SAS exome AF: 0.0392

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0178 AC: 25980 AN: 1459368 Hom.: 329 Cov.: 31 AF XY: 0.0186 AC XY: 13499 AN XY: 725936

Gnomad4 AFR exome AF: 0.00269

Gnomad4 AMR exome AF: 0.00530

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0416

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.0179

Gnomad4 OTH exome AF: 0.0173

GnomAD4 genome AF: 0.0122 AC: 1850 AN: 152242 Hom.: 18 Cov.: 31 AF XY: 0.0121 AC XY: 900 AN XY: 74444

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.0415

Gnomad4 FIN AF: 0.0141

Gnomad4 NFE AF: 0.0170

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0142 Hom.: 9

Bravo AF: 0.0105

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0197

EpiControl AF: 0.0199

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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 specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Pseudoxanthoma elasticum, forme fruste Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Arterial calcification, generalized, of infancy, 2 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	-0.90
CADD	Benign	0.015
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs58760581; hg19: chr16-16248476;