rs72664283

chr16-16202100-T-Cchr16-16202100-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001171.6(ABCC6):c.1077A>G(p.Ser359=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,610,970 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S359S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (74 hom.)
• Consequence: ABCC6 NM_001171.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.32

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=-0.89).
• BP6: Variant 16-16202100-T-C is Benign according to our data. Variant chr16-16202100-T-C is described in ClinVar as [Benign]. Clinvar id is 379234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (2031/152224) while in subpopulation AFR AF= 0.0395 (1639/41494). AF 95% confidence interval is 0.0379. There are 38 homozygotes in gnomad4. There are 1031 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 38 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.1077A>G	p.Ser359=	synonymous_variant	9/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.735A>G	p.Ser245=	synonymous_variant	9/31
ABCC6	NR_147784.1	n.1114A>G		non_coding_transcript_exon_variant	9/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.1077A>G	p.Ser359=	synonymous_variant	9/31	1	NM_001171.6	P1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2023 AN: 152108 Hom.: 38 Cov.: 31

Gnomad AFR AF: 0.0394

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00559 AC: 1402 AN: 250716 Hom.: 21 AF XY: 0.00526 AC XY: 713 AN XY: 135482

Gnomad AFR exome AF: 0.0374

Gnomad AMR exome AF: 0.00458

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00256

Gnomad SAS exome AF: 0.0121

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00274 AC: 4001 AN: 1458746 Hom.: 74 Cov.: 32 AF XY: 0.00295 AC XY: 2142 AN XY: 725700

Gnomad4 AFR exome AF: 0.0298

Gnomad4 AMR exome AF: 0.00513

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00277

Gnomad4 SAS exome AF: 0.0124

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00488

GnomAD4 genome AF: 0.0133 AC: 2031 AN: 152224 Hom.: 38 Cov.: 31 AF XY: 0.0138 AC XY: 1031 AN XY: 74442

Gnomad4 AFR AF: 0.0395

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00502

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00816 Hom.: 1

Bravo AF: 0.0150

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Benign:2

Benign, no assertion criteria provided	research	PXE International	Mar 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 19, 2016

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. -

Pseudoxanthoma elasticum, forme fruste Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.64
Dann	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs72664283; hg19: chr16-16295957;