16-16150095-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001171.6(ABCC6):c.*38G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,609,912 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (79 hom.)
• Consequence: ABCC6 NM_001171.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.00

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-16150095-C-T is Benign according to our data. Variant chr16-16150095-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 433370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16150095-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0021 (320/152336) while in subpopulation AMR AF= 0.0184 (281/15304). AF 95% confidence interval is 0.0166. There are 3 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.*38G>A		3_prime_UTR_variant	31/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.*38G>A		3_prime_UTR_variant	31/31
ABCC6	NR_147784.1	n.4212G>A		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.*38G>A		3_prime_UTR_variant	31/31	1	NM_001171.6	P1
ABCC6	ENST00000622290.5	c.*722G>A		3_prime_UTR_variant, NMD_transcript_variant	32/32	5
ABCC6	ENST00000456970.6			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 321 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00822 AC: 2012 AN: 244624 Hom.: 66 AF XY: 0.00613 AC XY: 815 AN XY: 132962

Gnomad AFR exome AF: 0.000328

Gnomad AMR exome AF: 0.0567

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00209

Gnomad SAS exome AF: 0.0000661

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000363

Gnomad OTH exome AF: 0.00515

GnomAD4 exome AF: 0.00179 AC: 2610 AN: 1457576 Hom.: 79 Cov.: 30 AF XY: 0.00150 AC XY: 1085 AN XY: 724976

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.0514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00545

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00209 AC XY: 156 AN XY: 74490

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000568 Hom.: 0

Bravo AF: 0.00500

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Benign:2

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001171.5:c.*38G>A in the ABCC6 gene has an allele frequency of 0.056 in Latino subpopulation in the gnomAD database. 66 homozygous occurrences are observed in the gnomAD database.This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2. -
Benign, no assertion criteria provided	research	PXE International	Mar 01, 2021	- -

ABCC6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.074
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs59461468; hg19: chr16-16243952;