rs72664288

chr16-16154788-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001171.6(ABCC6):c.4048A>C(p.Ile1350Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I1350I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.154

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 3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31754053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.4048A>C	p.Ile1350Leu	missense_variant	29/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.3706A>C	p.Ile1236Leu	missense_variant	29/31
ABCC6	NR_147784.1	n.3710A>C		non_coding_transcript_exon_variant	27/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.4048A>C	p.Ile1350Leu	missense_variant	29/31	1	NM_001171.6	P1
ABCC6	ENST00000576204.6	n.911A>C		non_coding_transcript_exon_variant	2/2	5
ABCC6	ENST00000456970.6	c.*1057A>C		3_prime_UTR_variant, NMD_transcript_variant	27/29	2
ABCC6	ENST00000622290.5	c.*220A>C		3_prime_UTR_variant, NMD_transcript_variant	30/32	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1459430 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1

Uncertain significance, criteria provided, single submitter

research

PXE International

Feb 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	11
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	-0.88	N;.
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.25
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.0070	D;.
Polyphen		0.032	B;.
Vest4		0.37
MutPred		0.65		Gain of catalytic residue at I1350 (P = 0.1131);.;
MVP		0.64
MPC		0.071
ClinPred		0.73	D
GERP RS		2.3
Varity_R		0.42
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs72664288; hg19: chr16-16248645;