16-16154654-C-G

Variant names:

• chr16-16154654-C-G
• rs63750798
• NM_001171.6:c.4182G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1 PM1 PM2

The NM_001171.6(ABCC6):​c.4182G>C​(p.Lys1394Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,122 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., 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 Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_001171.6 (ABCC6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a domain ABC transporter 2 (size 234) in uniprot entity MRP6_HUMAN there are 39 pathogenic changes around while only 5 benign (89%) in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.4182G>C	p.Lys1394Asn	missense_variant	Exon 29 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.3840G>C	p.Lys1280Asn	missense_variant	Exon 29 of 31		NP_001338729.1
ABCC6	NR_147784.1	n.3844G>C		non_coding_transcript_exon_variant	Exon 27 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.4182G>C	p.Lys1394Asn	missense_variant	Exon 29 of 31	1	NM_001171.6	ENSP00000205557.7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

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	0.44	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.0	L;.
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		0.35	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;