16-16165761-G-T

Variant names:

• chr16-16165761-G-T
• rs72657694
• NM_001171.6:c.3168C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001171.6(ABCC6):​c.3168C>A​(p.Asp1056Glu) variant causes a missense 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). Synonymous variant affecting the same amino acid position (i.e. D1056D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.724
• Publications: 5 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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 16-16165761-G-T is Pathogenic according to our data. Variant chr16-16165761-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433303.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.3168C>A	p.Asp1056Glu	missense	Exon 23 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.3135C>A	p.Asp1045Glu	missense	Exon 23 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.3000C>A	p.Asp1000Glu	missense	Exon 22 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.3168C>A	p.Asp1056Glu	missense	Exon 23 of 31	ENSP00000205557.7
	ABCC6	ENST00000909083.1		c.3264C>A	p.Asp1088Glu	missense	Exon 24 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.3261C>A	p.Asp1087Glu	missense	Exon 24 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	0.26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		-0.72
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.94		Gain of disorder (P = 0.1573)
MVP		0.64
MPC		0.38
ClinPred		0.98	D
GERP RS		-9.2
Varity_R		0.86
gMVP		0.67
Mutation Taster		=9/91	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: rs72657694; hg19: chr16-16259618;