chr16-16212173-G-A

Position:

• chr16-16212173-G-A

Variant summary

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

The ENST00000205557.12(ABCC6):​c.662+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0183 in 137,152 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (43 hom., cov: 23)
  • Exomes 𝑓: 0.024 (314 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC6 ENST00000205557.12 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.564

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]

LOC105371100 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-16212173-G-A is Benign according to our data. Variant chr16-16212173-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16212173-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0183 (2513/137152) while in subpopulation NFE AF= 0.0284 (1825/64332). AF 95% confidence interval is 0.0273. There are 43 homozygotes in gnomad4. There are 1120 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.662+12C>T		intron_variant		ENST00000205557.12	NP_001162.5
LOC105371100	XR_933131.3	n.282+82G>A		intron_variant, non_coding_transcript_variant
ABCC6	NM_001351800.1	c.320+12C>T		intron_variant			NP_001338729.1
ABCC6	NR_147784.1	n.699+12C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.662+12C>T		intron_variant		1	NM_001171.6	ENSP00000205557	P1

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2510 AN: 137078 Hom.: 43 Cov.: 23

Gnomad AFR AF: 0.00387

Gnomad AMI AF: 0.0139

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0172

Gnomad EAS AF: 0.00302

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00987

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0178

GnomAD3 exomes AF: 0.0166 AC: 2389 AN: 143728 Hom.: 35 AF XY: 0.0168 AC XY: 1289 AN XY: 76952

Gnomad AFR exome AF: 0.00297

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.00117

Gnomad SAS exome AF: 0.0143

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0193

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0244 AC: 16526 AN: 678232 Hom.: 314 Cov.: 9 AF XY: 0.0241 AC XY: 8707 AN XY: 361336

Gnomad4 AFR exome AF: 0.00527

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.00616

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.0243

Gnomad4 NFE exome AF: 0.0294

Gnomad4 OTH exome AF: 0.0244

GnomAD4 genome AF: 0.0183 AC: 2513 AN: 137152 Hom.: 43 Cov.: 23 AF XY: 0.0169 AC XY: 1120 AN XY: 66356

Gnomad4 AFR AF: 0.00386

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.0172

Gnomad4 EAS AF: 0.00303

Gnomad4 SAS AF: 0.00994

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.0284

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0265 Hom.: 19

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ABCC6 c.662+12C>T variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs72664291), ClinVar (reported likely benign by GeneDx and pathogenic by PXE International), Clinvitae, and LOVD 3.0 (classified as benign). The variant was identified in control databases in 2838 of 169536 chromosomes (42 homozygous) at a frequency of 0.01674 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 1691 of 65948 chromosomes (freq: 0.02564), Other in 93 of 4902 chromosomes (freq: 0.01897), European (Finnish) in 326 of 18338 chromosomes (freq: 0.01778), South Asian in 310 of 21710 chromosomes (freq: 0.01428), Ashkenazi Jewish in 103 of 7726 chromosomes (freq: 0.01333), Latino in 256 of 24756 chromosomes (freq: 0.01034), African in 44 of 13714 chromosomes (freq: 0.003208), and East Asian in 15 of 12442 chromosomes (freq: 0.001206). The c.662+12C>T variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive inherited pseudoxanthoma elasticum Benign:1

Benign, no assertion criteria provided

research

PXE International

Mar 01, 2021

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.4
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555520951; hg19: chr16-16306030;