rs72657698

chr16-16208729-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001171.6(ABCC6):c.793A>G(p.Arg265Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0666 in 151,816 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (358 hom., cov: 30)
  • Exomes 𝑓: 0.037 (3822 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC6 NM_001171.6 missense, splice_region
• Scores: Splicing: ADA: 0.008483
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0140

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 (MetaRNN=0.0022835135).
• BP6: Variant 16-16208729-T-C is Benign according to our data. Variant chr16-16208729-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in Lovd as [Benign]. Variant chr16-16208729-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.793A>G	p.Arg265Gly	missense_variant, splice_region_variant	7/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.451A>G	p.Arg151Gly	missense_variant, splice_region_variant	7/31
ABCC6	NR_147784.1	n.830A>G		splice_region_variant, non_coding_transcript_exon_variant	7/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.793A>G	p.Arg265Gly	missense_variant, splice_region_variant	7/31	1	NM_001171.6	P1

Frequencies

GnomAD3 genomes AF: 0.0666 AC: 10110 AN: 151698 Hom.: 359 Cov.: 30

Gnomad AFR AF: 0.0599

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0601

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.0329

Gnomad SAS AF: 0.0264

Gnomad FIN AF: 0.0448

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0802

Gnomad OTH AF: 0.0685

GnomAD3 exomes AF: 0.0427 AC: 10355 AN: 242738 Hom.: 511 AF XY: 0.0431 AC XY: 5647 AN XY: 131142

Gnomad AFR exome AF: 0.0482

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.0312

Gnomad EAS exome AF: 0.0231

Gnomad SAS exome AF: 0.0137

Gnomad FIN exome AF: 0.0378

Gnomad NFE exome AF: 0.0603

Gnomad OTH exome AF: 0.0465

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0366 AC: 49797 AN: 1360146 Hom.: 3822 Cov.: 33 AF XY: 0.0372 AC XY: 25224 AN XY: 678628

Gnomad4 AFR exome AF: 0.0333

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.0501

Gnomad4 EAS exome AF: 0.0427

Gnomad4 SAS exome AF: 0.0199

Gnomad4 FIN exome AF: 0.0479

Gnomad4 NFE exome AF: 0.0371

Gnomad4 OTH exome AF: 0.0409

GnomAD4 genome AF: 0.0666 AC: 10108 AN: 151816 Hom.: 358 Cov.: 30 AF XY: 0.0644 AC XY: 4777 AN XY: 74192

Gnomad4 AFR AF: 0.0598

Gnomad4 AMR AF: 0.0600

Gnomad4 ASJ AF: 0.0709

Gnomad4 EAS AF: 0.0330

Gnomad4 SAS AF: 0.0262

Gnomad4 FIN AF: 0.0448

Gnomad4 NFE AF: 0.0802

Gnomad4 OTH AF: 0.0678

Alfa AF: 0.0763 Hom.: 114

Bravo AF: 0.0681

ExAC AF: 0.0600 AC: 7282

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Benign:3

Benign, criteria provided, single submitter	research	PXE International	Mar 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 29, 2015	This variant was found once in our laboratory in trans with a pathogenic variant [R518X] in a 39-year-old male with hereditary anemia, angioid streaks on retina, possible pseudoxanthoma elasticum, fatigue, chronic joint pain. However, variant is common, and we have identified homozygotes who do not have features of PXE. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:3

Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 19726431, 27884173, 11536079, 16086317, 19339160, 33144682) -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	1.9
Dann	Benign	0.74
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.46	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.082
Sift	Benign	0.48	T;.
Sift4G	Benign	0.29	T;T
Polyphen		0.0	B;.
Vest4		0.056
MPC		0.085
ClinPred		0.0025	T
GERP RS		-1.0
Varity_R		0.055
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0085
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs72657698; hg19: chr16-16302586; COSMIC: COSV52741028;