rs63750209

Variant names:

• chr16-16157727-C-T
• rs63750209
• NM_001171.6:c.3818G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001171.6(ABCC6):​c.3818G>A​(p.Arg1273Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. R1273R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.40
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.3818G>A	p.Arg1273Lys	missense_variant	Exon 27 of 31	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.3818G>A	p.Arg1273Lys	missense_variant	Exon 27 of 31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000456970.6	n.*827G>A		non_coding_transcript_exon_variant	Exon 25 of 29	2		ENSP00000405002.2
ABCC6	ENST00000622290.5	n.3818G>A		non_coding_transcript_exon_variant	Exon 27 of 32	5		ENSP00000483331.2
ABCC6	ENST00000456970.6	n.*827G>A		3_prime_UTR_variant	Exon 25 of 29	2		ENSP00000405002.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1

Feb 16, 2021

PXE International

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.
Eigen	Benign	-0.013
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.82	L;.
PhyloP100		4.4
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.041	D;.
Polyphen		0.54	P;.
Vest4		0.30
MutPred		0.66		Gain of ubiquitination at R1273 (P = 0.03);.;
MVP		0.89
MPC		0.29
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.58
gMVP		0.76
Mutation Taster		=65/35	polymorphism

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: rs63750209; hg19: chr16-16251584;