rs3902401

Variant names:

• chr16-16150116-C-T
• rs3902401
• NM_001171.6:c.*17G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001171.6(ABCC6):​c.*17G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0657 in 1,611,476 control chromosomes in the GnomAD database, including 3,972 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.059 (335 hom., cov: 33)
  • Exomes 𝑓: 0.066 (3637 hom.)
• Consequence: ABCC6 NM_001171.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.70
• Publications: 6 publications found

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]

ABCC6 Gene-Disease associations (from GenCC):

• arterial calcification, generalized, of infancy, 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• autosomal recessive inherited pseudoxanthoma elasticum

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• arterial calcification of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.*17G>A		3_prime_UTR_variant	Exon 31 of 31	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.*17G>A		3_prime_UTR_variant	Exon 31 of 31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000622290.5	n.*701G>A		non_coding_transcript_exon_variant	Exon 32 of 32	5		ENSP00000483331.2
ABCC6	ENST00000622290.5	n.*701G>A		3_prime_UTR_variant	Exon 32 of 32	5		ENSP00000483331.2
ABCC6	ENST00000456970.6	n.*1538G>A		downstream_gene_variant		2		ENSP00000405002.2

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 8958 AN: 152114 Hom.: 335 Cov.: 33

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0632

Gnomad ASJ AF: 0.0821

Gnomad EAS AF: 0.0517

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0279

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0668

Gnomad OTH AF: 0.0630

GnomAD2 exomes AF: 0.0663 AC: 16445 AN: 247926 AF XY: 0.0724

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.0411

Gnomad ASJ exome AF: 0.0811

Gnomad EAS exome AF: 0.0436

Gnomad FIN exome AF: 0.0292

Gnomad NFE exome AF: 0.0659

Gnomad OTH exome AF: 0.0698

GnomAD4 exome AF: 0.0664 AC: 96836 AN: 1459244 Hom.: 3637 Cov.: 30 AF XY: 0.0688 AC XY: 49940 AN XY: 725894

African (AFR) AF: 0.0375 AC: 1252 AN: 33406

American (AMR) AF: 0.0434 AC: 1937 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0835 AC: 2181 AN: 26118

East Asian (EAS) AF: 0.0628 AC: 2493 AN: 39682

South Asian (SAS) AF: 0.144 AC: 12364 AN: 86088

European-Finnish (FIN) AF: 0.0300 AC: 1590 AN: 52998

Middle Eastern (MID) AF: 0.0931 AC: 407 AN: 4372

European-Non Finnish (NFE) AF: 0.0633 AC: 70413 AN: 1111716

Other (OTH) AF: 0.0698 AC: 4199 AN: 60186

GnomAD4 genome AF: 0.0589 AC: 8960 AN: 152232 Hom.: 335 Cov.: 33 AF XY: 0.0604 AC XY: 4498 AN XY: 74436

African (AFR) AF: 0.0390 AC: 1621 AN: 41526

American (AMR) AF: 0.0631 AC: 965 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0821 AC: 285 AN: 3472

East Asian (EAS) AF: 0.0514 AC: 266 AN: 5172

South Asian (SAS) AF: 0.151 AC: 727 AN: 4824

European-Finnish (FIN) AF: 0.0279 AC: 296 AN: 10618

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0668 AC: 4542 AN: 68008

Other (OTH) AF: 0.0614 AC: 130 AN: 2116

Alfa AF: 0.0631 Hom.: 589

Bravo AF: 0.0568

Asia WGS AF: 0.0950 AC: 333 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

Mar 01, 2021

PXE International

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pseudoxanthoma elasticum, forme fruste Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arterial calcification, generalized, of infancy, 2 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.20
DANN	Benign	0.50
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3902401; hg19: chr16-16243973; COSMIC: COSV105066000; COSMIC: COSV105066000;