rs72653765

Variant names:

• chr16-16198115-A-G
• rs72653765
• NM_001171.6:c.1244T>C

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). Synonymous variant affecting the same amino acid position (i.e. V415V) has been classified as Benign.

• 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 8 pathogenic changes around while only 2 benign (80%) 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 rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.1244T>C	p.Val415Ala	missense_variant	Exon 10 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.902T>C	p.Val301Ala	missense_variant	Exon 10 of 31		NP_001338729.1
ABCC6	NR_147784.1	n.1281T>C		non_coding_transcript_exon_variant	Exon 10 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.1244T>C	p.Val415Ala	missense_variant	Exon 10 of 31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000574094.6	c.1244T>C	p.Val415Ala	missense_variant	Exon 10 of 11	5		ENSP00000507301.1
ABCC6	ENST00000456970.6	n.1244T>C		non_coding_transcript_exon_variant	Exon 10 of 29	2		ENSP00000405002.2
ABCC6	ENST00000622290.5	n.1244T>C		non_coding_transcript_exon_variant	Exon 10 of 32	5		ENSP00000483331.2

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

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	0.31
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
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;