16-16154767-G-C

Variant names:

• chr16-16154767-G-C
• rs63750428
• NM_001171.6:c.4069C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001171.6(ABCC6):​c.4069C>G​(p.Arg1357Gly) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1357Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-16154766-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1359254.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

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.4069C>G	p.Arg1357Gly	missense	Exon 29 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.4036C>G	p.Arg1346Gly	missense	Exon 29 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.3901C>G	p.Arg1301Gly	missense	Exon 28 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.4069C>G	p.Arg1357Gly	missense	Exon 29 of 31	ENSP00000205557.7
	ABCC6	ENST00000456970.6	TSL:2	n.*1078C>G		non_coding_transcript_exon	Exon 27 of 29	ENSP00000405002.2
	ABCC6	ENST00000576204.6	TSL:5	n.932C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.52	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.0
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.81		Loss of catalytic residue at R1357 (P = 0.0179)
MVP		0.87
MPC		0.46
ClinPred		1.0	D
GERP RS		-2.8
Varity_R		0.69
gMVP		0.94
Mutation Taster		=24/76	disease causing

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: rs63750428; hg19: chr16-16248624;