chr16-16150095-C-T

Variant names:

• chr16-16150095-C-T
• rs59461468
• NM_001171.6:c.*38G>A

Variant summary

Our verdict is Benign. The variant received -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: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.00
• Publications: 0 publications found

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]

ABCC6 Gene-Disease associations (from GenCC):

• arterial calcification, generalized, of infancy, 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• autosomal recessive inherited pseudoxanthoma elasticum

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• arterial calcification of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 433370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.*38G>A		3_prime_UTR_variant	Exon 31 of 31	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.*38G>A		3_prime_UTR_variant	Exon 31 of 31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000622290.5	n.*722G>A		non_coding_transcript_exon_variant	Exon 32 of 32	5		ENSP00000483331.2
ABCC6	ENST00000622290.5	n.*722G>A		3_prime_UTR_variant	Exon 32 of 32	5		ENSP00000483331.2
ABCC6	ENST00000456970.6	n.*1559G>A		downstream_gene_variant		2		ENSP00000405002.2

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

GnomAD2 exomes AF: 0.00822 AC: 2012 AN: 244624 AF XY: 0.00613

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 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

African (AFR) AF: 0.000330 AC: 11 AN: 33378

American (AMR) AF: 0.0514 AC: 2282 AN: 44356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00545 AC: 216 AN: 39646

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4206

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111094

Other (OTH) AF: 0.00131 AC: 79 AN: 60118

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

African (AFR) AF: 0.000553 AC: 23 AN: 41576

American (AMR) AF: 0.0184 AC: 281 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000915 Hom.: 1

Bravo AF: 0.00500

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Benign:2

Mar 01, 2021

PXE International

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

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.

ABCC6-related disorder Benign:1

Jul 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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).

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Jan 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.074
DANN	Benign	0.58
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs59461468; hg19: chr16-16243952;