rs72653765

Positions:

• chr16-16198115-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001171.6(ABCC6):​c.1244T>C​(p.Val415Ala) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V415M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.33

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 55) in uniprot entity MRP6_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.1244T>C	p.Val415Ala	missense_variant	10/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.902T>C	p.Val301Ala	missense_variant	10/31
ABCC6	NR_147784.1	n.1281T>C		non_coding_transcript_exon_variant	10/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.1244T>C	p.Val415Ala	missense_variant	10/31	1	NM_001171.6	P1
ABCC6	ENST00000574094.6	c.1244T>C	p.Val415Ala	missense_variant	10/11	5
ABCC6	ENST00000622290.5	c.1244T>C	p.Val415Ala	missense_variant, NMD_transcript_variant	10/32	5
ABCC6	ENST00000456970.6	c.1244T>C	p.Val415Ala	missense_variant, NMD_transcript_variant	10/29	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 51

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1

Uncertain significance, no assertion criteria provided

research

PXE International

Feb 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.085
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.036	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Pathogenic	0.73
Sift	Benign	0.064	T;.
Sift4G	Benign	0.18	T;D
Polyphen		0.44	B;.
Vest4		0.71
MutPred		0.79		Loss of stability (P = 0.0188);Loss of stability (P = 0.0188);
MVP		0.82
MPC		0.39
ClinPred		0.74	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.62

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: rs72653765; hg19: chr16-16291972;