dbSNP rs72657691: ABCC6:p.Arg964Leu (chr16-16169750-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001171.6(ABCC6):c.2891G>T(p.Arg964Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R964P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.438

Publications

0 publications found

Variant links:

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

ABCC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.35953498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6 link	c.2891G>T	p.Arg964Leu	missense_variant	Exon 22 of 31	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ABCC6	ENST00000205557.12 link	c.2891G>T	p.Arg964Leu	missense_variant	Exon 22 of 31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000456970.6 link	n.*100G>T		non_coding_transcript_exon_variant	Exon 21 of 29	2		ENSP00000405002.2
ABCC6	ENST00000622290.5 link	n.2891G>T		non_coding_transcript_exon_variant	Exon 22 of 32	5		ENSP00000483331.2
ABCC6	ENST00000456970.6 link	n.*100G>T		3_prime_UTR_variant	Exon 21 of 29	2		ENSP00000405002.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452850

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33292

American (AMR)

AF:

0.00

AC:

AN:

43422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25934

East Asian (EAS)

AF:

0.00

AC:

AN:

39172

South Asian (SAS)

AF:

0.00

AC:

AN:

84936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5558

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108358

Other (OTH)

AF:

0.00

AC:

AN:

60032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.36

MetaSVM

Uncertain

-0.031

MutationAssessor

Benign

2.0

PhyloP100

0.44

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.0

REVEL

Pathogenic

0.65

Sift

Benign

0.074

Sift4G

Benign

0.34

Polyphen

0.21

Vest4

0.25

MutPred

0.74

Gain of helix (P = 0.2294);

MVP

0.81

MPC

0.095

ClinPred

0.63

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.52

Mutation Taster

=58/42

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over