16-16150272-T-C

Variant names:

• chr16-16150272-T-C
• rs212097
• NM_001171.6:c.4404-31A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001171.6(ABCC6):​c.4404-31A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 1,612,620 control chromosomes in the GnomAD database, including 147,010 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.36 (11290 hom., cov: 33)
  • Exomes 𝑓: 0.43 (135720 hom.)
• Consequence: ABCC6 NM_001171.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0390
• Publications: 20 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-16150272-T-C is Benign according to our data. Variant chr16-16150272-T-C is described in ClinVar as Benign. ClinVar VariationId is 1245693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.4404-31A>G		intron_variant	Intron 30 of 30	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.4404-31A>G		intron_variant	Intron 30 of 30	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000456970.6	n.*1413-31A>G		intron_variant	Intron 28 of 28	2		ENSP00000405002.2
ABCC6	ENST00000622290.5	n.*576-31A>G		intron_variant	Intron 31 of 31	5		ENSP00000483331.2

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54653 AN: 152012 Hom.: 11287 Cov.: 33

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.375

GnomAD2 exomes AF: 0.395 AC: 97477 AN: 246794 AF XY: 0.400

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.406

Gnomad ASJ exome AF: 0.433

Gnomad EAS exome AF: 0.169

Gnomad FIN exome AF: 0.461

Gnomad NFE exome AF: 0.455

Gnomad OTH exome AF: 0.415

GnomAD4 exome AF: 0.426 AC: 622079 AN: 1460490 Hom.: 135720 Cov.: 55 AF XY: 0.425 AC XY: 308969 AN XY: 726524

African (AFR) AF: 0.146 AC: 4885 AN: 33468

American (AMR) AF: 0.410 AC: 18287 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 11329 AN: 26126

East Asian (EAS) AF: 0.208 AC: 8255 AN: 39688

South Asian (SAS) AF: 0.358 AC: 30839 AN: 86212

European-Finnish (FIN) AF: 0.450 AC: 23851 AN: 52956

Middle Eastern (MID) AF: 0.374 AC: 2148 AN: 5750

European-Non Finnish (NFE) AF: 0.448 AC: 498062 AN: 1111396

Other (OTH) AF: 0.405 AC: 24423 AN: 60344

GnomAD4 genome AF: 0.359 AC: 54671 AN: 152130 Hom.: 11290 Cov.: 33 AF XY: 0.361 AC XY: 26822 AN XY: 74352

African (AFR) AF: 0.160 AC: 6653 AN: 41532

American (AMR) AF: 0.429 AC: 6549 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 1522 AN: 3472

East Asian (EAS) AF: 0.176 AC: 911 AN: 5166

South Asian (SAS) AF: 0.356 AC: 1716 AN: 4822

European-Finnish (FIN) AF: 0.468 AC: 4950 AN: 10578

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.455 AC: 30935 AN: 67970

Other (OTH) AF: 0.371 AC: 782 AN: 2110

Alfa AF: 0.426 Hom.: 25215

Bravo AF: 0.343

Asia WGS AF: 0.276 AC: 964 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive inherited pseudoxanthoma elasticum Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.81
CADD	Benign	1.1
DANN	Benign	0.75
PhyloP100		0.039
BranchPoint Hunter		3.0
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)		0.060		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: rs212097; hg19: chr16-16244129; COSMIC: COSV52744226;