16-16154873-C-T

Variant names:

• chr16-16154873-C-T
• rs63751111
• NM_001171.6:c.4041G>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001171.6(ABCC6):​c.4041G>A​(p.Gln1347Gln) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ABCC6 NM_001171.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.9985
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.89

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-16154873-C-T is Pathogenic according to our data. Variant chr16-16154873-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 599399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.4041G>A	p.Gln1347Gln	splice_region_variant, synonymous_variant	Exon 28 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.3699G>A	p.Gln1233Gln	splice_region_variant, synonymous_variant	Exon 28 of 31		NP_001338729.1
ABCC6	NR_147784.1	n.3703G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 26 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.4041G>A	p.Gln1347Gln	splice_region_variant, synonymous_variant	Exon 28 of 31	1	NM_001171.6	ENSP00000205557.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000814 AC: 2 AN: 245790 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460506 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726434

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1

-

Medical Genetics UMG, Mater Domini University Hospital/ Magna Graecia University of Catanzaro

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

c.4041 G>A variant affects the splicing of exon 28 of ABCC6 gene generating an mRNA with a skipped exon 28 (our in vitro study). In vitro functional studies indicate the significance of exon 28 of ABCC6 because a significant decrease in the ABCC6 transport activity was detected in three mutants generated with changes in residues encoded by the exon 28 (PMID:11880368). This variant has a frequency of 2/241074 alleles in the gnomAD database. This variant is present in a homozygous state in two affected siblings and their heterozygous parents are not affected. -

not provided Pathogenic:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 1347 of the ABCC6 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ABCC6 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs63751111, gnomAD 0.002%). This variant has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 31240106). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 599399). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 28, but is expected to preserve the integrity of the reading-frame (PMID: 31240106). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.55		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63751111; hg19: chr16-16248730;