rs72657699

Positions:

• chr16-16203453-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001171.6(ABCC6):​c.955A>G​(p.Ile319Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,612,760 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (12 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.36

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 Benign. Variant got -18 ACMG points.

• PM1: In a domain ABC transmembrane type-1 1 (size 282) in uniprot entity MRP6_HUMAN there are 54 pathogenic changes around while only 20 benign (73%) in NM_001171.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.003887266).
• BP6: Variant 16-16203453-T-C is Benign according to our data. Variant chr16-16203453-T-C is described in ClinVar as [Benign]. Clinvar id is 388992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16203453-T-C is described in Lovd as [Benign]. Variant chr16-16203453-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00701 (1066/152096) while in subpopulation AFR AF= 0.0235 (973/41374). AF 95% confidence interval is 0.0223. There are 8 homozygotes in gnomad4. There are 520 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.955A>G	p.Ile319Val	missense_variant	8/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.613A>G	p.Ile205Val	missense_variant	8/31
ABCC6	NR_147784.1	n.992A>G		non_coding_transcript_exon_variant	8/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.955A>G	p.Ile319Val	missense_variant	8/31	1	NM_001171.6	P1

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 1065 AN: 151980 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00127 AC: 318 AN: 250582 Hom.: 3 AF XY: 0.00111 AC XY: 150 AN XY: 135504

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00563

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000406 AC: 593 AN: 1460664 Hom.: 12 Cov.: 32 AF XY: 0.000402 AC XY: 292 AN XY: 726782

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.000806

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00278

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.000978

GnomAD4 genome AF: 0.00701 AC: 1066 AN: 152096 Hom.: 8 Cov.: 32 AF XY: 0.00699 AC XY: 520 AN XY: 74378

Gnomad4 AFR AF: 0.0235

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00464

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00334 Hom.: 0

ExAC AF: 0.00189 AC: 229

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	research	PXE International	Mar 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2019	This variant is associated with the following publications: (PMID: 12384774, 16086317, 11536079) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Pseudoxanthoma elasticum, forme fruste Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Arterial calcification, generalized, of infancy, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.012
DANN	Benign	0.49
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.14	T;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.84	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.0	N;.
REVEL	Benign	0.21
Sift	Benign	0.96	T;.
Sift4G	Benign	0.79	T;T
Polyphen		0.0	B;.
Vest4		0.025
MVP		0.44
MPC		0.058
ClinPred		0.0028	T
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs72657699; hg19: chr16-16297310;