rs9940825

Positions:

• chr16-16198114-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001171.6(ABCC6):​c.1245G>A​(p.Val415=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,611,634 control chromosomes in the GnomAD database, including 87,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7118 hom., cov: 33)
  • Exomes 𝑓: 0.33 (80315 hom.)
• Consequence: ABCC6 NM_001171.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.804

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 16-16198114-C-T is Benign according to our data. Variant chr16-16198114-C-T is described in ClinVar as [Benign]. Clinvar id is 433228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16198114-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.804 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.1245G>A	p.Val415=	synonymous_variant	10/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.903G>A	p.Val301=	synonymous_variant	10/31
ABCC6	NR_147784.1	n.1282G>A		non_coding_transcript_exon_variant	10/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.1245G>A	p.Val415=	synonymous_variant	10/31	1	NM_001171.6	P1
ABCC6	ENST00000574094.6	c.1245G>A	p.Val415=	synonymous_variant	10/11	5
ABCC6	ENST00000622290.5	c.1245G>A	p.Val415=	synonymous_variant, NMD_transcript_variant	10/32	5
ABCC6	ENST00000456970.6	c.1245G>A	p.Val415=	synonymous_variant, NMD_transcript_variant	10/29	2

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45196 AN: 152046 Hom.: 7122 Cov.: 33

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.0959

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.306

GnomAD3 exomes AF: 0.285 AC: 70039 AN: 245644 Hom.: 10523 AF XY: 0.286 AC XY: 38093 AN XY: 133078

Gnomad AFR exome AF: 0.256

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.0947

Gnomad SAS exome AF: 0.217

Gnomad FIN exome AF: 0.306

Gnomad NFE exome AF: 0.347

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.326 AC: 475529 AN: 1459470 Hom.: 80315 Cov.: 51 AF XY: 0.323 AC XY: 234251 AN XY: 725842

Gnomad4 AFR exome AF: 0.249

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.223

Gnomad4 EAS exome AF: 0.0903

Gnomad4 SAS exome AF: 0.219

Gnomad4 FIN exome AF: 0.314

Gnomad4 NFE exome AF: 0.352

Gnomad4 OTH exome AF: 0.296

GnomAD4 genome AF: 0.297 AC: 45189 AN: 152164 Hom.: 7118 Cov.: 33 AF XY: 0.291 AC XY: 21661 AN XY: 74398

Gnomad4 AFR AF: 0.253

Gnomad4 AMR AF: 0.294

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.0959

Gnomad4 SAS AF: 0.207

Gnomad4 FIN AF: 0.310

Gnomad4 NFE AF: 0.347

Gnomad4 OTH AF: 0.302

Alfa AF: 0.327 Hom.: 10780

Bravo AF: 0.294

Asia WGS AF: 0.148 AC: 513 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

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, no assertion criteria provided	research	PXE International	Mar 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Pseudoxanthoma elasticum, forme fruste Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.4
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs9940825; hg19: chr16-16291971; COSMIC: COSV52741162; COSMIC: COSV52741162;