rs72653801

Variant names:

• chr16-16169810-G-A
• rs72653801
• NM_001171.6:c.2831C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-16169810-G-A
• chr16-16169810-G-C
• chr16-16169810-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001171.6(ABCC6):​c.2831C>T​(p.Thr944Ile) 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 benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0330
• Publications: 2 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39659435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.2831C>T	p.Thr944Ile	missense_variant	Exon 22 of 31	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.2831C>T	p.Thr944Ile	missense_variant	Exon 22 of 31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000456970.6	n.*40C>T		non_coding_transcript_exon_variant	Exon 21 of 29	2		ENSP00000405002.2
ABCC6	ENST00000622290.5	n.2831C>T		non_coding_transcript_exon_variant	Exon 22 of 32	5		ENSP00000483331.2
ABCC6	ENST00000456970.6	n.*40C>T		3_prime_UTR_variant	Exon 21 of 29	2		ENSP00000405002.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1

Feb 16, 2021

PXE International

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	0.71
DANN	Benign	0.65
DEOGEN2	Benign	0.082	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.85	L
PhyloP100		-0.033
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.41	N
REVEL	Uncertain	0.55
Sift	Benign	0.34	T
Sift4G	Benign	0.41	T
Polyphen		0.0040	B
Vest4		0.71
MutPred		0.53		Loss of glycosylation at T944 (P = 0.1136);
MVP		0.56
MPC		0.072
ClinPred		0.85	D
GERP RS		-7.7
Varity_R		0.056
gMVP		0.17
Mutation Taster		=40/60	disease causing

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: rs72653801; hg19: chr16-16263667;