rs63750798

Positions:

• chr16-16154654-C-A
• chr16-16154654-C-G
• chr16-16154654-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.735

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-16154654-C-A is Pathogenic according to our data. Variant chr16-16154654-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.4182G>T	p.Lys1394Asn	missense_variant	29/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.3840G>T	p.Lys1280Asn	missense_variant	29/31
ABCC6	NR_147784.1	n.3844G>T		non_coding_transcript_exon_variant	27/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.4182G>T	p.Lys1394Asn	missense_variant	29/31	1	NM_001171.6	P1
ABCC6	ENST00000456970.6	c.*1191G>T		3_prime_UTR_variant, NMD_transcript_variant	27/29	2
ABCC6	ENST00000622290.5	c.*354G>T		3_prime_UTR_variant, NMD_transcript_variant	30/32	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.54	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.96	N;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0080	D;.
Polyphen		0.60	P;.
Vest4		0.81
MutPred		0.77		Loss of ubiquitination at K1394 (P = 0.0167);.;
MVP		0.81
MPC		0.083
ClinPred		0.39	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.60

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: rs63750798; hg19: chr16-16248511;