16-16150161-C-G

Position:

• chr16-16150161-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001171.6(ABCC6):​c.4484G>C​(p.Arg1495Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

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 2 ACMG points.

• PM1: In a domain ABC transporter 2 (size 234) in uniprot entity MRP6_HUMAN there are 72 pathogenic changes around while only 8 benign (90%) in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19828752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.4484G>C	p.Arg1495Thr	missense_variant	31/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.4142G>C	p.Arg1381Thr	missense_variant	31/31
ABCC6	NR_147784.1	n.4146G>C		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.4484G>C	p.Arg1495Thr	missense_variant	31/31	1	NM_001171.6	P1
ABCC6	ENST00000456970.6	c.*1493G>C		3_prime_UTR_variant, NMD_transcript_variant	29/29	2
ABCC6	ENST00000622290.5	c.*656G>C		3_prime_UTR_variant, NMD_transcript_variant	32/32	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249968 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135546

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460832 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726706

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 24, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC6 protein function. This variant has not been reported in the literature in individuals affected with ABCC6-related conditions. This variant is present in population databases (rs756250178, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 1495 of the ABCC6 protein (p.Arg1495Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.82	L;.
MutationTaster	Benign	0.83	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.14
Sift	Benign	0.35	T;.
Sift4G	Benign	0.57	T;.
Polyphen		0.57	P;.
Vest4		0.21
MutPred		0.48		Gain of methylation at K1490 (P = 0.043);.;
MVP		0.76
MPC		0.10
ClinPred		0.32	T
GERP RS		4.8
Varity_R		0.27
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs756250178; hg19: chr16-16244018;