rs3213471

chr16-16161580-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001171.6(ABCC6):c.3507-16T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,613,748 control chromosomes in the GnomAD database, including 1,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (442 hom., cov: 32)
  • Exomes 𝑓: 0.016 (620 hom.)
• Consequence: ABCC6 NM_001171.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.139

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=-0.88).
• BP6: Variant 16-16161580-A-G is Benign according to our data. Variant chr16-16161580-A-G is described in ClinVar as [Benign]. Clinvar id is 433392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16161580-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.3507-16T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000205557.12
ABCC6	NM_001351800.1	c.3165-16T>C		splice_polypyrimidine_tract_variant, intron_variant
ABCC6	NR_147784.1	n.3169-16T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.3507-16T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001171.6	P1
ABCC6	ENST00000456970.6	c.*516-16T>C		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2
ABCC6	ENST00000622290.5	c.3507-16T>C		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0484 AC: 7363 AN: 152136 Hom.: 435 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.0721

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00867

Gnomad OTH AF: 0.0464

GnomAD3 exomes AF: 0.0254 AC: 6335 AN: 249622 Hom.: 250 AF XY: 0.0232 AC XY: 3133 AN XY: 135228

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0284

Gnomad EAS exome AF: 0.0715

Gnomad SAS exome AF: 0.0302

Gnomad FIN exome AF: 0.000741

Gnomad NFE exome AF: 0.00878

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0159 AC: 23170 AN: 1461494 Hom.: 620 Cov.: 34 AF XY: 0.0157 AC XY: 11389 AN XY: 727026

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0250

Gnomad4 EAS exome AF: 0.0653

Gnomad4 SAS exome AF: 0.0288

Gnomad4 FIN exome AF: 0.00104

Gnomad4 NFE exome AF: 0.00928

Gnomad4 OTH exome AF: 0.0274

GnomAD4 genome AF: 0.0485 AC: 7391 AN: 152254 Hom.: 442 Cov.: 32 AF XY: 0.0474 AC XY: 3527 AN XY: 74446

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0310

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.0719

Gnomad4 SAS AF: 0.0332

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00867

Gnomad4 OTH AF: 0.0540

Alfa AF: 0.0187 Hom.: 88

Bravo AF: 0.0546

Asia WGS AF: 0.113 AC: 392 AN: 3478

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	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	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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	-0.88
Cadd	Benign	1.8
Dann	Benign	0.54
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: rs3213471; hg19: chr16-16255437;