rs78678589

chr16-16203457-G-Cchr16-16203457-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5

The NM_001171.6(ABCC6):c.951C>G(p.Ser317Arg) 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 Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S317?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.73

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PS1: Transcript NM_001171.6 (ABCC6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 433366
• PM1: In a domain ABC transmembrane type-1 1 (size 282) in uniprot entity MRP6_HUMAN there are 54 pathogenic changes around while only 20 benign (73%) 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 chr16-16203457-G-Y is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 16-16203457-G-C is Pathogenic according to our data. Variant chr16-16203457-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 433374.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.951C>G	p.Ser317Arg	missense_variant	8/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.609C>G	p.Ser203Arg	missense_variant	8/31
ABCC6	NR_147784.1	n.988C>G		non_coding_transcript_exon_variant	8/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.951C>G	p.Ser317Arg	missense_variant	8/31	1	NM_001171.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1

Pathogenic, no assertion criteria provided

research

PXE International

Mar 01, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.86	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.86	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.2	N;.
REVEL	Pathogenic	0.76
Sift	Benign	0.084	T;.
Sift4G	Benign	0.11	T;D
Polyphen		0.95	P;.
Vest4		0.85
MutPred		0.93		Gain of methylation at S317 (P = 0.0168);Gain of methylation at S317 (P = 0.0168);
MVP		0.88
MPC		0.17
ClinPred		0.75	D
GERP RS		2.3
Varity_R		0.72
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs78678589; hg19: chr16-16297314;