NM_001171.6:c.2836_2851delCTCTGCCTCTACGCAC

Variant names:

• chr16-16169789-AGTGCGTAGAGGCAGAG-A
• rs74315152
• NM_001171.6:c.2836_2851delCTCTGCCTCTACGCAC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001171.6(ABCC6):​c.2836_2851delCTCTGCCTCTACGCAC​(p.Leu946SerfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC6 NM_001171.6 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.11
• 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: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• arterial calcification of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-16169789-AGTGCGTAGAGGCAGAG-A is Pathogenic according to our data. Variant chr16-16169789-AGTGCGTAGAGGCAGAG-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433412.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.2836_2851delCTCTGCCTCTACGCAC	p.Leu946SerfsTer18	frameshift	Exon 22 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.2803_2818delCTCTGCCTCTACGCAC	p.Leu935SerfsTer18	frameshift	Exon 22 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.2668_2683delCTCTGCCTCTACGCAC	p.Leu890SerfsTer18	frameshift	Exon 21 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.2836_2851delCTCTGCCTCTACGCAC	p.Leu946SerfsTer18	frameshift	Exon 22 of 31	ENSP00000205557.7
	ABCC6	ENST00000909083.1		c.2836_2851delCTCTGCCTCTACGCAC	p.Leu946SerfsTer18	frameshift	Exon 22 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.2836_2851delCTCTGCCTCTACGCAC	p.Leu946SerfsTer18	frameshift	Exon 22 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

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
PhyloP100		3.1
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs74315152; hg19: chr16-16263646;