rs72653753

Variant names:

• chr16-16219642-C-T
• rs72653753
• NM_001171.6:c.386G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001171.6(ABCC6):​c.386G>A​(p.Gly129Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000326 in 1,502,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.85
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.386G>A	p.Gly129Glu	missense_variant	Exon 4 of 31	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.386G>A	p.Gly129Glu	missense_variant	Exon 4 of 31	1	NM_001171.6	ENSP00000205557.7

Frequencies

GnomAD3 genomes AF: 0.0000200 AC: 3 AN: 150314 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000518 AC: 3 AN: 57906 AF XY: 0.0000683

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000340 AC: 46 AN: 1352434 Hom.: 0 Cov.: 25 AF XY: 0.0000299 AC XY: 20 AN XY: 669972

African (AFR) AF: 0.0000329 AC: 1 AN: 30386

American (AMR) AF: 0.00 AC: 0 AN: 36040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24926

East Asian (EAS) AF: 0.00 AC: 0 AN: 35956

South Asian (SAS) AF: 0.0000510 AC: 4 AN: 78410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3964

European-Non Finnish (NFE) AF: 0.0000355 AC: 37 AN: 1041048

Other (OTH) AF: 0.0000709 AC: 4 AN: 56436

GnomAD4 genome AF: 0.0000200 AC: 3 AN: 150314 Hom.: 0 Cov.: 24 AF XY: 0.0000273 AC XY: 2 AN XY: 73228

African (AFR) AF: 0.00 AC: 0 AN: 40644

American (AMR) AF: 0.00 AC: 0 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67676

Other (OTH) AF: 0.00 AC: 0 AN: 2040

Alfa AF: 0.0000638 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1

Mar 01, 2021

PXE International

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.4	M;M
PhyloP100		4.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.2	D;.
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.72		Gain of ubiquitination at K127 (P = 0.0561);Gain of ubiquitination at K127 (P = 0.0561);
MVP		0.74
MPC		2.8
ClinPred		0.94	D
GERP RS		4.4
Varity_R		0.80
gMVP		0.65
Mutation Taster		=22/78	disease causing (ClinVar)

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: rs72653753; hg19: chr16-16313499;