Genetic Variant NM_001171.6:c.4182G>T (chr16-16154654-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001171.6(ABCC6):c.4182G>T(p.Lys1394Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K1394K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.735

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCC6	NM_001171.6	MANE Select	c.4182G>T	p.Lys1394Asn	missense	Exon 29 of 31	NP_001162.5
ABCC6	NM_001440309.1		c.4149G>T	p.Lys1383Asn	missense	Exon 29 of 31	NP_001427238.1
ABCC6	NM_001440310.1		c.4014G>T	p.Lys1338Asn	missense	Exon 28 of 30	NP_001427239.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.4182G>T	p.Lys1394Asn	missense	Exon 29 of 31	ENSP00000205557.7
ABCC6	ENST00000456970.6	TSL:2	n.*1191G>T		non_coding_transcript_exon	Exon 27 of 29	ENSP00000405002.2
ABCC6	ENST00000622290.5	TSL:5	n.*354G>T		non_coding_transcript_exon	Exon 30 of 32	ENSP00000483331.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.47

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.0

PhyloP100

0.73

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.96

REVEL

Uncertain

0.30

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0080

Polyphen

0.60

Vest4

0.81

MutPred

0.77

Loss of ubiquitination at K1394 (P = 0.0167)

MVP

0.81

MPC

0.083

ClinPred

0.39

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.60

Mutation Taster

=17/83

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over