rs41278174

chr16-16165739-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001171.6(ABCC6):c.3190C>T(p.Arg1064Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,613,760 control chromosomes in the GnomAD database, including 587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1064Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (34 hom., cov: 33)
  • Exomes 𝑓: 0.025 (553 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:14
• Conservation: PhyloP100: 3.53

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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001171.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.010730177).
• BP6: Variant 16-16165739-G-A is Benign according to our data. Variant chr16-16165739-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16165739-G-A is described in Lovd as [Benign]. Variant chr16-16165739-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0175 (2670/152336) while in subpopulation SAS AF= 0.0317 (153/4828). AF 95% confidence interval is 0.0276. There are 34 homozygotes in gnomad4. There are 1358 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.3190C>T	p.Arg1064Trp	missense_variant	23/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.2848C>T	p.Arg950Trp	missense_variant	23/31
ABCC6	NR_147784.1	n.3052C>T		non_coding_transcript_exon_variant	22/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.3190C>T	p.Arg1064Trp	missense_variant	23/31	1	NM_001171.6	P1
ABCC6	ENST00000622290.5	c.3190C>T	p.Arg1064Trp	missense_variant, NMD_transcript_variant	23/32	5
ABCC6	ENST00000456970.6	c.*399C>T		3_prime_UTR_variant, NMD_transcript_variant	22/29	2

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2669 AN: 152218 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.0207 AC: 5197 AN: 251186 Hom.: 78 AF XY: 0.0216 AC XY: 2940 AN XY: 135888

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00867

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0311

Gnomad FIN exome AF: 0.0356

Gnomad NFE exome AF: 0.0244

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0248 AC: 36279 AN: 1461424 Hom.: 553 Cov.: 33 AF XY: 0.0250 AC XY: 18157 AN XY: 726986

Gnomad4 AFR exome AF: 0.00341

Gnomad4 AMR exome AF: 0.00912

Gnomad4 ASJ exome AF: 0.0209

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0311

Gnomad4 FIN exome AF: 0.0340

Gnomad4 NFE exome AF: 0.0262

Gnomad4 OTH exome AF: 0.0242

GnomAD4 genome AF: 0.0175 AC: 2670 AN: 152336 Hom.: 34 Cov.: 33 AF XY: 0.0182 AC XY: 1358 AN XY: 74478

Gnomad4 AFR AF: 0.00430

Gnomad4 AMR AF: 0.00935

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0317

Gnomad4 FIN AF: 0.0364

Gnomad4 NFE AF: 0.0246

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0230 Hom.: 92

Bravo AF: 0.0148

TwinsUK AF: 0.0254 AC: 94

ALSPAC AF: 0.0246 AC: 95

ESP6500AA AF: 0.00410 AC: 18

ESP6500EA AF: 0.0243 AC: 209

ExAC AF: 0.0205 AC: 2488

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jun 06, 2023	- -
Benign, no assertion criteria provided	research	PXE International	Oct 05, 2021	- -
Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ABCC6: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31456290, 16086317, 25264593) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Pseudoxanthoma elasticum, forme fruste 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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	0.92	D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.010	D;.
Sift4G	Uncertain	0.026	D;.
Polyphen		1.0	D;.
Vest4		0.25
MPC		0.38
ClinPred		0.041	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.55

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: rs41278174; hg19: chr16-16259596; COSMIC: COSV52744032;