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 16 ACMG points: 17P and 1B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000321369: Published functional studies demonstrate a damaging effect with R1314W resulting in abnormal protein trafficking and inappropriate intracellular accumulation (Le Saux et al., 2011)" and additional evidence is available in ClinVar. 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: 28 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000321369: Published functional studies demonstrate a damaging effect with R1314W resulting in abnormal protein trafficking and inappropriate intracellular accumulation (Le Saux et al., 2011); PMID: 16392638; SCV001587439: Experimental studies have shown that this missense change affects ABCC6 function (PMID: 21935449, 23483032, 27994049).
• 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;