16-16182484-T-A

Position:

• chr16-16182484-T-A

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.2175A>T​(p.Val725=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,614,148 control chromosomes in the GnomAD database, including 420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (81 hom., cov: 32)
  • Exomes 𝑓: 0.016 (339 hom.)
• Consequence: ABCC6 NM_001171.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.263

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=-0.73).
• BP6: Variant 16-16182484-T-A is Benign according to our data. Variant chr16-16182484-T-A is described in ClinVar as [Benign]. Clinvar id is 433262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16182484-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.263 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.2175A>T	p.Val725=	synonymous_variant	17/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.1833A>T	p.Val611=	synonymous_variant	17/31		NP_001338729.1
ABCC6	NR_147784.1	n.2212A>T		non_coding_transcript_exon_variant	17/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.2175A>T	p.Val725=	synonymous_variant	17/31	1	NM_001171.6	ENSP00000205557	P1
ABCC6	ENST00000622290.5	c.2175A>T	p.Val725=	synonymous_variant, NMD_transcript_variant	17/32	5		ENSP00000483331
ABCC6	ENST00000456970.6	c.2175A>T	p.Val725=	synonymous_variant, NMD_transcript_variant	17/29	2		ENSP00000405002

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3772 AN: 152168 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0371

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0163 AC: 4107 AN: 251452 Hom.: 91 AF XY: 0.0172 AC XY: 2343 AN XY: 135908

Gnomad AFR exome AF: 0.0524

Gnomad AMR exome AF: 0.00830

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0362

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.0162 AC: 23691 AN: 1461862 Hom.: 339 Cov.: 33 AF XY: 0.0168 AC XY: 12227 AN XY: 727228

Gnomad4 AFR exome AF: 0.0569

Gnomad4 AMR exome AF: 0.00890

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0378

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.0193

GnomAD4 genome AF: 0.0248 AC: 3778 AN: 152286 Hom.: 81 Cov.: 32 AF XY: 0.0239 AC XY: 1779 AN XY: 74458

Gnomad4 AFR AF: 0.0542

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.0132

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0369

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.0138

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0157 Hom.: 17

Bravo AF: 0.0268

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0180

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2019	This variant is associated with the following publications: (PMID: 16127278, 16086317, 15723264, 19339160) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Autosomal recessive inherited pseudoxanthoma elasticum Benign:2

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

not specified Benign:2

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

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	-0.73
CADD	Benign	0.11
DANN	Benign	0.58

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: rs59757815; hg19: chr16-16276341;