rs41278172

chr16-16161567-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001171.6(ABCC6):c.3507-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,613,868 control chromosomes in the GnomAD database, including 357 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (31 hom., cov: 32)
  • Exomes 𝑓: 0.018 (326 hom.)
• Consequence: ABCC6 NM_001171.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.02283
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.36

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 16-16161567-G-A is Benign according to our data. Variant chr16-16161567-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 281169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16161567-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-16161567-G-A is described in Lovd as [Benign]. Variant chr16-16161567-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0154 (2342/152296) while in subpopulation SAS AF= 0.0238 (115/4826). AF 95% confidence interval is 0.0203. There are 31 homozygotes in gnomad4. There are 1200 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.3507-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000205557.12
ABCC6	NM_001351800.1	c.3165-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ABCC6	NR_147784.1	n.3169-3C>T		splice_region_variant, 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.3507-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001171.6	P1
ABCC6	ENST00000456970.6	c.*516-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2
ABCC6	ENST00000622290.5	c.3507-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2342 AN: 152178 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.0368

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0164 AC: 4100 AN: 250166 Hom.: 38 AF XY: 0.0174 AC XY: 2354 AN XY: 135440

Gnomad AFR exome AF: 0.00315

Gnomad AMR exome AF: 0.00868

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0217

Gnomad FIN exome AF: 0.0319

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0181 AC: 26517 AN: 1461572 Hom.: 326 Cov.: 34 AF XY: 0.0184 AC XY: 13359 AN XY: 727062

Gnomad4 AFR exome AF: 0.00266

Gnomad4 AMR exome AF: 0.00868

Gnomad4 ASJ exome AF: 0.0152

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0218

Gnomad4 FIN exome AF: 0.0305

Gnomad4 NFE exome AF: 0.0189

Gnomad4 OTH exome AF: 0.0173

GnomAD4 genome AF: 0.0154 AC: 2342 AN: 152296 Hom.: 31 Cov.: 32 AF XY: 0.0161 AC XY: 1200 AN XY: 74474

Gnomad4 AFR AF: 0.00354

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0238

Gnomad4 FIN AF: 0.0368

Gnomad4 NFE AF: 0.0207

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0169 Hom.: 15

Bravo AF: 0.0122

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0188

EpiControl AF: 0.0187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ABCC6: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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	- -

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

- -

Finnish congenital nephrotic syndrome Benign:1

Likely benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous c.3507-3C>T variant in ABCC6 has been reported in at least 2 individuals with autosomal recessive pseudoxanthoma elasticum (PMID: 16835894). It has also been identified in >3% of European (Finnish) chromosomes and 14 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive pseudoxanthoma elasticum. -

Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	11
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.023
dbscSNV1_RF	Benign	0.65
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: rs41278172; hg19: chr16-16255424;