16-16208841-G-C

Variant names:

• chr16-16208841-G-C
• rs1315925055
• NM_001171.6:c.681C>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.681C>G​(p.Tyr227*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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: 31)
• Consequence: ABCC6 NM_001171.6 stop_gained
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.16
• Publications: 1 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

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 16-16208841-G-C is Pathogenic according to our data. Variant chr16-16208841-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433402.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	NM_001171.6	MANE Select	c.681C>G	p.Tyr227*	stop_gained	Exon 7 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.681C>G	p.Tyr227*	stop_gained	Exon 7 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.681C>G	p.Tyr227*	stop_gained	Exon 7 of 30	NP_001427239.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.681C>G	p.Tyr227*	stop_gained	Exon 7 of 31	ENSP00000205557.7
	ABCC6	ENST00000574094.6	TSL:5	c.681C>G	p.Tyr227*	stop_gained	Exon 7 of 11	ENSP00000507301.1
	ABCC6	ENST00000456970.6	TSL:2	n.681C>G		non_coding_transcript_exon	Exon 7 of 29	ENSP00000405002.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		3.2
Vest4		0.70
GERP RS		4.1
Mutation Taster		=0/200	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: rs1315925055; hg19: chr16-16302698;