rs2239319

Variant names:

• chr16-16214494-G-A
• rs2239319
• NM_001171.6:c.475-45C>T

Variant summary

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

The NM_001171.6(ABCC6):​c.475-45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,551,506 control chromosomes in the GnomAD database, including 2,883 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 0.028 (353 hom., cov: 29)
  • Exomes 𝑓: 0.026 (2530 hom.)
• Consequence: ABCC6 NM_001171.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.579
• 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

ENSG00000305554 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.475-45C>T		intron_variant	Intron 4 of 30	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.475-45C>T		intron_variant	Intron 4 of 30	1	NM_001171.6	ENSP00000205557.7

Frequencies

GnomAD3 genomes AF: 0.0280 AC: 4253 AN: 152144 Hom.: 353 Cov.: 29

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.00668

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0580 AC: 9010 AN: 155428 AF XY: 0.0586

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.0822

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.322

Gnomad FIN exome AF: 0.00462

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0351

GnomAD4 exome AF: 0.0262 AC: 36665 AN: 1399244 Hom.: 2530 Cov.: 32 AF XY: 0.0280 AC XY: 19318 AN XY: 690138

African (AFR) AF: 0.0114 AC: 359 AN: 31594

American (AMR) AF: 0.0746 AC: 2665 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 452 AN: 25176

East Asian (EAS) AF: 0.316 AC: 11284 AN: 35750

South Asian (SAS) AF: 0.0905 AC: 7174 AN: 79230

European-Finnish (FIN) AF: 0.00519 AC: 256 AN: 49294

Middle Eastern (MID) AF: 0.0343 AC: 195 AN: 5692

European-Non Finnish (NFE) AF: 0.0112 AC: 12106 AN: 1078812

Other (OTH) AF: 0.0375 AC: 2174 AN: 57996

GnomAD4 genome AF: 0.0280 AC: 4256 AN: 152262 Hom.: 353 Cov.: 29 AF XY: 0.0317 AC XY: 2358 AN XY: 74442

African (AFR) AF: 0.0121 AC: 504 AN: 41558

American (AMR) AF: 0.0398 AC: 608 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3470

East Asian (EAS) AF: 0.335 AC: 1731 AN: 5160

South Asian (SAS) AF: 0.104 AC: 499 AN: 4818

European-Finnish (FIN) AF: 0.00668 AC: 71 AN: 10624

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 716 AN: 68022

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.0167 Hom.: 15

Bravo AF: 0.0320

Asia WGS AF: 0.188 AC: 653 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.70
PhyloP100		0.58
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: rs2239319; hg19: chr16-16308351; COSMIC: COSV107223253;