16-16150200-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_001171.6(ABCC6):c.4445G>C(p.Ser1482Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,600 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1482R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20

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 0 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.13304934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.4445G>C	p.Ser1482Thr	missense_variant	31/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.4103G>C	p.Ser1368Thr	missense_variant	31/31
ABCC6	NR_147784.1	n.4107G>C		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.4445G>C	p.Ser1482Thr	missense_variant	31/31	1	NM_001171.6	P1
ABCC6	ENST00000456970.6	c.*1454G>C		3_prime_UTR_variant, NMD_transcript_variant	29/29	2
ABCC6	ENST00000622290.5	c.*617G>C		3_prime_UTR_variant, NMD_transcript_variant	32/32	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461600 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Feb 23, 2022

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1482 of the ABCC6 protein (p.Ser1482Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ABCC6-related conditions. 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) performed at Invitae indicates that this missense variant is not expected to disrupt ABCC6 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	18
Dann	Benign	0.95
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.30	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.76	N;.
REVEL	Benign	0.028
Sift	Benign	0.21	T;.
Sift4G	Benign	0.43	T;.
Polyphen		0.47	P;.
Vest4		0.059
MutPred		0.25		Loss of disorder (P = 0.0617);.;
MVP		0.64
MPC		0.077
ClinPred		0.22	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-16244057;