chr16-16163078-G-A

Variant names:

• chr16-16163078-G-A
• rs72653706
• NM_001171.6:c.3421C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PVS1 PS3 PP5_Very_Strong BS2_Supporting

The NM_001171.6(ABCC6):​c.3421C>T​(p.Arg1141*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,922 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV006557217: which is supported by experimental studies performed on cells derived from patients with pseudoxanthoma elasticum." and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: ABCC6 NM_001171.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:34 O:1
• Conservation: PhyloP100: 3.00
• Publications: 114 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 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV006557217: which is supported by experimental studies performed on cells derived from patients with pseudoxanthoma elasticum.; SCV000321366: Expression studies of the R1141X variant in leukocytes and cultured fibroblasts from affected individuals homozygous for R1141X demonstrate mRNA instability and absence of the protein in immunohistochemistry studies (Hu et al., 2003);; SCV002583665: PS3, PM3_Strong no
• PP5: Variant 16-16163078-G-A is Pathogenic according to our data. Variant chr16-16163078-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3421C>T	p.Arg1141*	stop_gained	Exon 24 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.3388C>T	p.Arg1130*	stop_gained	Exon 24 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.3253C>T	p.Arg1085*	stop_gained	Exon 23 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.3421C>T	p.Arg1141*	stop_gained	Exon 24 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.3517C>T	p.Arg1173*	stop_gained	Exon 25 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.3514C>T	p.Arg1172*	stop_gained	Exon 25 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00141 AC: 355 AN: 251296 AF XY: 0.00154

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00166 AC: 2431 AN: 1461600 Hom.: 5 Cov.: 33 AF XY: 0.00171 AC XY: 1245 AN XY: 727076

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00282 AC: 150 AN: 53140

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00195 AC: 2166 AN: 1112002

Other (OTH) AF: 0.00136 AC: 82 AN: 60392

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74490

African (AFR) AF: 0.000241 AC: 10 AN: 41576

American (AMR) AF: 0.000980 AC: 15 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00198 Hom.: 1

Bravo AF: 0.00108

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00139 AC: 169

EpiCase AF: 0.00191

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	not provided (13)
11	-	-	Autosomal recessive inherited pseudoxanthoma elasticum (11)
3	-	-	Arterial calcification, generalized, of infancy, 2 (3)
3	-	-	Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2;CN032334:Autosomal recessive inherited pseudoxanthoma elasticum (3)
2	-	-	ABCC6-related disorder (2)
1	-	-	Cutis laxa;C0332563:Papule (1)
1	-	-	See cases (1)
-	-	-	Pseudoxanthoma elasticum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		3.0
Vest4		0.89
GERP RS		4.4
Mutation Taster		=1/199	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: rs72653706; hg19: chr16-16256935;