rs1555513103

Variant names:

• chr16-16182533-T-C
• rs1555513103
• NM_001171.6:c.2126A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_001171.6(ABCC6):​c.2126A>G​(p.Glu709Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.01

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 4 ACMG points.

• PM1: In a domain ABC transporter 1 (size 224) in uniprot entity MRP6_HUMAN there are 31 pathogenic changes around while only 5 benign (86%) in NM_001171.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.2126A>G	p.Glu709Gly	missense_variant	Exon 17 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.1784A>G	p.Glu595Gly	missense_variant	Exon 17 of 31		NP_001338729.1
ABCC6	NR_147784.1	n.2163A>G		non_coding_transcript_exon_variant	Exon 17 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.2126A>G	p.Glu709Gly	missense_variant	Exon 17 of 31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000456970.6	n.2126A>G		non_coding_transcript_exon_variant	Exon 17 of 29	2		ENSP00000405002.2
ABCC6	ENST00000622290.5	n.2126A>G		non_coding_transcript_exon_variant	Exon 17 of 32	5		ENSP00000483331.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727238

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1

Feb 16, 2021

PXE International

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.92	P;.
Vest4		0.47
MutPred		0.71		Loss of stability (P = 0.0641);Loss of stability (P = 0.0641);
MVP		0.89
MPC		0.12
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.52
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555513103; hg19: chr16-16276390;