rs59157279

Variant names:

• chr16-16190259-C-T
• rs59157279
• NM_001171.6:c.1540G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-16190259-C-T
• chr16-16190259-C-A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001171.6(ABCC6):​c.1540G>A​(p.Val514Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000693 in 1,614,144 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00071 (6 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 1.65
• Publications: 15 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet
• inherited pseudoxanthoma elasticum

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• arterial calcification of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001171.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.012797385).
• BP6: Variant 16-16190259-C-T is Benign according to our data. Variant chr16-16190259-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 433236.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000709 (1036/1461880) while in subpopulation MID AF = 0.0102 (59/5768). AF 95% confidence interval is 0.00814. There are 6 homozygotes in GnomAdExome4. There are 580 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	NM_001171.6	MANE Select	c.1540G>A	p.Val514Ile	missense	Exon 12 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.1540G>A	p.Val514Ile	missense	Exon 12 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.1540G>A	p.Val514Ile	missense	Exon 12 of 30	NP_001427239.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.1540G>A	p.Val514Ile	missense	Exon 12 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.1540G>A	p.Val514Ile	missense	Exon 12 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.1540G>A	p.Val514Ile	missense	Exon 12 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152146 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00106 AC: 267 AN: 251330 AF XY: 0.00118

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000607

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000709 AC: 1036 AN: 1461880 Hom.: 6 Cov.: 35 AF XY: 0.000798 AC XY: 580 AN XY: 727238

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.00163 AC: 73 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 65 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00328 AC: 283 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5768

European-Non Finnish (NFE) AF: 0.000425 AC: 473 AN: 1112010

Other (OTH) AF: 0.00124 AC: 75 AN: 60396

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152264 Hom.: 0 Cov.: 31 AF XY: 0.000591 AC XY: 44 AN XY: 74446

African (AFR) AF: 0.000313 AC: 13 AN: 41572

American (AMR) AF: 0.000785 AC: 12 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000880 Hom.: 5

Bravo AF: 0.000688

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000980 AC: 119

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	-	ABCC6-related disorder (1)
-	-	1	Autosomal recessive inherited pseudoxanthoma elasticum (1)
-	-	1	not specified (1)
-	-	1	Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2;CN032334:Autosomal recessive inherited pseudoxanthoma elasticum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.63	N
PhyloP100		1.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.16
Sift	Benign	0.18	T
Sift4G	Benign	0.29	T
Polyphen		0.17	B
Vest4		0.15
MVP		0.55
MPC		0.065
ClinPred		0.0075	T
GERP RS		0.16
Varity_R		0.053
gMVP		0.52
Mutation Taster		=85/15	polymorphism

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: rs59157279; hg19: chr16-16284116;