rs2606921

Positions:

• chr16-16219555-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001171.6(ABCC6):​c.473C>T​(p.Ala158Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 149,362 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A158A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (20 hom., cov: 25)
  • Exomes 𝑓: 0.0014 (53 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC6 NM_001171.6 missense, splice_region
• Scores: Splicing: ADA: 0.0001696
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.12

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14915383).
• BP6: Variant 16-16219555-G-A is Benign according to our data. Variant chr16-16219555-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16219555-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1607/149362) while in subpopulation AFR AF= 0.0236 (943/39932). AF 95% confidence interval is 0.0224. There are 20 homozygotes in gnomad4. There are 722 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.473C>T	p.Ala158Val	missense_variant, splice_region_variant	4/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.131C>T	p.Ala44Val	missense_variant, splice_region_variant	4/31
ABCC6	NR_147784.1	n.510C>T		splice_region_variant, non_coding_transcript_exon_variant	4/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.473C>T	p.Ala158Val	missense_variant, splice_region_variant	4/31	1	NM_001171.6	P1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1606 AN: 149250 Hom.: 20 Cov.: 25

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00763

Gnomad ASJ AF: 0.00500

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00974

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.0107

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00145 AC: 2069 AN: 1431380 Hom.: 53 Cov.: 31 AF XY: 0.00145 AC XY: 1028 AN XY: 710286

Gnomad4 AFR exome AF: 0.00867

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.00248

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.00213

Gnomad4 FIN exome AF: 0.000998

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.00284

GnomAD4 genome AF: 0.0108 AC: 1607 AN: 149362 Hom.: 20 Cov.: 25 AF XY: 0.00989 AC XY: 722 AN XY: 73012

Gnomad4 AFR AF: 0.0236

Gnomad4 AMR AF: 0.00769

Gnomad4 ASJ AF: 0.00500

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00975

Gnomad4 FIN AF: 0.00161

Gnomad4 NFE AF: 0.00607

Gnomad4 OTH AF: 0.0106

Alfa AF: 0.00794 Hom.: 3

ExAC AF: 0.0000262 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Benign:1

Likely benign, no assertion criteria provided

research

PXE International

Feb 02, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 28, 2021

This variant is associated with the following publications: (PMID: 28655553, 31589614, 16392638, 16086317) -

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

Sep 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.031
Sift	Benign	0.23	T;.
Sift4G	Benign	0.26	T;D
Polyphen		0.17	B;.
Vest4		0.20
MutPred		0.24		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.45
MPC		1.3
ClinPred		0.0098	T
GERP RS		3.4
Varity_R		0.034
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.098
SpliceAI score (max)		0.050		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: rs2606921; hg19: chr16-16313412; COSMIC: COSV52744913; COSMIC: COSV52744913;