rs63750759

Variant names:

• chr16-16154974-G-A
• rs63750759
• NM_001171.6:c.3940C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-16154974-G-A
• chr16-16154974-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PM5 PP3 PP5_Very_Strong BP4

The NM_001171.6(ABCC6):​c.3940C>T​(p.Arg1314Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,576,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1314Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.32
• Publications: 26 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001171.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-16154973-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402332.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• PP5: Variant 16-16154974-G-A is Pathogenic according to our data. Variant chr16-16154974-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3097675). . Strength limited to SUPPORTING due to the PP5.

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.3940C>T	p.Arg1314Trp	missense	Exon 28 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.3907C>T	p.Arg1303Trp	missense	Exon 28 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.3772C>T	p.Arg1258Trp	missense	Exon 27 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.3940C>T	p.Arg1314Trp	missense	Exon 28 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.4036C>T	p.Arg1346Trp	missense	Exon 29 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.4033C>T	p.Arg1345Trp	missense	Exon 29 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152108 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000189 AC: 35 AN: 184926 AF XY: 0.0000904

Gnomad AFR exome AF: 0.00218

Gnomad AMR exome AF: 0.0000714

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000363

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000259

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000793 AC: 113 AN: 1424726 Hom.: 0 Cov.: 32 AF XY: 0.0000723 AC XY: 51 AN XY: 705360

African (AFR) AF: 0.00233 AC: 76 AN: 32584

American (AMR) AF: 0.000102 AC: 4 AN: 39342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25424

East Asian (EAS) AF: 0.000133 AC: 5 AN: 37460

South Asian (SAS) AF: 0.000111 AC: 9 AN: 81348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50050

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5724

European-Non Finnish (NFE) AF: 0.00000914 AC: 10 AN: 1093730

Other (OTH) AF: 0.000135 AC: 8 AN: 59064

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152226 Hom.: 0 Cov.: 31 AF XY: 0.000564 AC XY: 42 AN XY: 74426

African (AFR) AF: 0.00214 AC: 89 AN: 41546

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000672

ESP6500AA AF: 0.000686 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000216 AC: 26

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Autosomal recessive inherited pseudoxanthoma elasticum (2)
1	-	-	Arterial calcification, generalized, of infancy, 2 (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	0.23
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.31	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		1.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.96
MPC		0.42
ClinPred		0.33	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.94
Mutation Taster		=22/78	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs63750759; hg19: chr16-16248831; COSMIC: COSV52742951;