rs879956688

Variant names:

• chr16-16219655-C-A
• rs879956688
• NM_001171.6:c.373G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-16219655-C-A
• chr16-16219655-C-T
• chr16-16219655-C-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001171.6(ABCC6):​c.373G>T​(p.Glu125*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.000013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC6 NM_001171.6 stop_gained
• 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: 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

ENSG00000305554 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-16219655-C-A is Pathogenic according to our data. Variant chr16-16219655-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433415.Status of the report is no_assertion_criteria_provided, 0 stars.

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.373G>T	p.Glu125*	stop_gained	Exon 4 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.373G>T	p.Glu125*	stop_gained	Exon 4 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.373G>T	p.Glu125*	stop_gained	Exon 4 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.373G>T	p.Glu125*	stop_gained	Exon 4 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.373G>T	p.Glu125*	stop_gained	Exon 4 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.373G>T	p.Glu125*	stop_gained	Exon 4 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.0000176 AC: 1 AN: 56732 AF XY: 0.0000349

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000132 AC: 18 AN: 1364486 Hom.: 0 Cov.: 25 AF XY: 0.0000252 AC XY: 17 AN XY: 675212

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30648

American (AMR) AF: 0.00 AC: 0 AN: 35958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25034

East Asian (EAS) AF: 0.00 AC: 0 AN: 36002

South Asian (SAS) AF: 0.000229 AC: 18 AN: 78686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4000

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1053202

Other (OTH) AF: 0.00 AC: 0 AN: 56908

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000008468), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive inherited pseudoxanthoma elasticum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		4.8
Vest4		0.92
GERP RS		4.4
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 27

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879956688; hg19: chr16-16313512;