16-16185091-C-T

Variant names:

• chr16-16185091-C-T
• rs41278182
• NM_001171.6:c.1868-57G>A

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.1868-57G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,507,676 control chromosomes in the GnomAD database, including 65,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4903 hom., cov: 33)
  • Exomes 𝑓: 0.29 (60181 hom.)
• Consequence: ABCC6 NM_001171.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.874
• Publications: 4 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: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-16185091-C-T is Benign according to our data. Variant chr16-16185091-C-T is described in ClinVar as Benign. ClinVar VariationId is 1691110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.1868-57G>A		intron_variant	Intron 14 of 30	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.1868-57G>A		intron_variant	Intron 14 of 30	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000456970.6	n.1868-57G>A		intron_variant	Intron 14 of 28	2		ENSP00000405002.2
ABCC6	ENST00000622290.5	n.1868-57G>A		intron_variant	Intron 14 of 31	5		ENSP00000483331.2

Frequencies

GnomAD3 genomes AF: 0.233 AC: 34180 AN: 146870 Hom.: 4896 Cov.: 33

Gnomad AFR AF: 0.0807

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.515

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.290 AC: 394806 AN: 1360680 Hom.: 60181 AF XY: 0.296 AC XY: 201917 AN XY: 681648

African (AFR) AF: 0.0695 AC: 2187 AN: 31474

American (AMR) AF: 0.320 AC: 14053 AN: 43882

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 6826 AN: 25474

East Asian (EAS) AF: 0.450 AC: 17713 AN: 39340

South Asian (SAS) AF: 0.504 AC: 42770 AN: 84884

European-Finnish (FIN) AF: 0.326 AC: 17232 AN: 52808

Middle Eastern (MID) AF: 0.318 AC: 1649 AN: 5188

European-Non Finnish (NFE) AF: 0.270 AC: 275384 AN: 1020450

Other (OTH) AF: 0.297 AC: 16992 AN: 57180

GnomAD4 genome AF: 0.233 AC: 34192 AN: 146996 Hom.: 4903 Cov.: 33 AF XY: 0.243 AC XY: 17429 AN XY: 71632

African (AFR) AF: 0.0805 AC: 3233 AN: 40170

American (AMR) AF: 0.261 AC: 3756 AN: 14410

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 934 AN: 3408

East Asian (EAS) AF: 0.521 AC: 2595 AN: 4984

South Asian (SAS) AF: 0.516 AC: 2428 AN: 4706

European-Finnish (FIN) AF: 0.347 AC: 3458 AN: 9954

Middle Eastern (MID) AF: 0.297 AC: 82 AN: 276

European-Non Finnish (NFE) AF: 0.258 AC: 17104 AN: 66194

Other (OTH) AF: 0.227 AC: 460 AN: 2022

Alfa AF: 0.130 Hom.: 239

Bravo AF: 0.211

Asia WGS AF: 0.465 AC: 1616 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.8
DANN	Benign	0.46
PhyloP100		0.87
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: rs41278182; hg19: chr16-16278948; COSMIC: COSV52748064;