rs151187637

chr16-16192837-T-Achr16-16192837-T-C

Variant summary

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

The NM_001171.6(ABCC6):c.1424A>T(p.His475Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,613,706 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.481

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 topological_domain Cytoplasmic (size 61) in uniprot entity MRP6_HUMAN there are 14 pathogenic changes around while only 5 benign (74%) in NM_001171.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.1215654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.1424A>T	p.His475Leu	missense_variant	11/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.1082A>T	p.His361Leu	missense_variant	11/31
ABCC6	NR_147784.1	n.1461A>T		non_coding_transcript_exon_variant	11/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.1424A>T	p.His475Leu	missense_variant	11/31	1	NM_001171.6	P1
ABCC6	ENST00000622290.5	c.1424A>T	p.His475Leu	missense_variant, NMD_transcript_variant	11/32	5
ABCC6	ENST00000456970.6	c.1424A>T	p.His475Leu	missense_variant, NMD_transcript_variant	11/29	2

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000255 AC: 64 AN: 251146 Hom.: 0 AF XY: 0.000214 AC XY: 29 AN XY: 135744

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000579

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: 0.000485

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000296 AC: 432 AN: 1461654 Hom.: 0 Cov.: 31 AF XY: 0.000292 AC XY: 212 AN XY: 727146

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000112

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: 0.000370

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000224 AC: 34 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74258

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000454 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000255 AC: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 17, 2016

- -

Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	16
Dann	Benign	0.61
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.3	N;.
REVEL	Uncertain	0.49
Sift	Benign	0.41	T;.
Sift4G	Benign	0.28	T;T
Polyphen		0.12	B;.
Vest4		0.32
MVP		0.81
MPC		0.082
ClinPred		0.021	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.63

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: rs151187637; hg19: chr16-16286694;