rs63750992

Variant names:

• chr16-16154982-C-T
• rs63750992
• NM_001171.6:c.3932G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001171.6(ABCC6):​c.3932G>A​(p.Gly1311Glu) variant causes a missense change. 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 Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.00

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain ABC transporter 2 (size 234) in uniprot entity MRP6_HUMAN there are 39 pathogenic changes around while only 5 benign (89%) in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.3932G>A	p.Gly1311Glu	missense_variant	Exon 28 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.3590G>A	p.Gly1197Glu	missense_variant	Exon 28 of 31		NP_001338729.1
ABCC6	NR_147784.1	n.3594G>A		non_coding_transcript_exon_variant	Exon 26 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.3932G>A	p.Gly1311Glu	missense_variant	Exon 28 of 31	1	NM_001171.6	ENSP00000205557.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.95	L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.013	D;.
Sift4G	Uncertain	0.039	D;.
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.88		Loss of glycosylation at S1310 (P = 0.0503);.;
MVP		0.92
MPC		0.37
ClinPred		0.97	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs63750992; hg19: chr16-16248839;