rs58668703

Variant names:

• chr16-16150727-C-T
• rs58668703
• NM_001171.6:c.4254G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001171.6(ABCC6):​c.4254G>A​(p.Arg1418Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,613,896 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1418R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0077 (10 hom., cov: 33)
  • Exomes 𝑓: 0.010 (100 hom.)
• Consequence: ABCC6 NM_001171.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.677
• Publications: 5 publications found

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]

ABCC6 Gene-Disease associations (from GenCC):

• arterial calcification, generalized, of infancy, 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• autosomal recessive inherited pseudoxanthoma elasticum

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet
• inherited pseudoxanthoma elasticum

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• arterial calcification of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 16-16150727-C-T is Benign according to our data. Variant chr16-16150727-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 433357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.677 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00768 (1170/152354) while in subpopulation NFE AF = 0.0129 (875/68044). AF 95% confidence interval is 0.0122. There are 10 homozygotes in GnomAd4. There are 533 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	NM_001171.6	MANE Select	c.4254G>A	p.Arg1418Arg	synonymous	Exon 30 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.4221G>A	p.Arg1407Arg	synonymous	Exon 30 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.4086G>A	p.Arg1362Arg	synonymous	Exon 29 of 30	NP_001427239.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.4254G>A	p.Arg1418Arg	synonymous	Exon 30 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.4350G>A	p.Arg1450Arg	synonymous	Exon 31 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.4347G>A	p.Arg1449Arg	synonymous	Exon 31 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.00769 AC: 1170 AN: 152236 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00711 AC: 1778 AN: 250098 AF XY: 0.00704

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00310

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00955

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00934

GnomAD4 exome AF: 0.0103 AC: 15001 AN: 1461542 Hom.: 100 Cov.: 34 AF XY: 0.00987 AC XY: 7177 AN XY: 727048

African (AFR) AF: 0.00185 AC: 62 AN: 33480

American (AMR) AF: 0.00329 AC: 147 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 120 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.000847 AC: 73 AN: 86222

European-Finnish (FIN) AF: 0.00937 AC: 499 AN: 53246

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.0122 AC: 13538 AN: 1111898

Other (OTH) AF: 0.00878 AC: 530 AN: 60390

GnomAD4 genome AF: 0.00768 AC: 1170 AN: 152354 Hom.: 10 Cov.: 33 AF XY: 0.00715 AC XY: 533 AN XY: 74506

African (AFR) AF: 0.00188 AC: 78 AN: 41580

American (AMR) AF: 0.00516 AC: 79 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00687 AC: 73 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0129 AC: 875 AN: 68044

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0105 Hom.: 14

Bravo AF: 0.00720

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0112

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Autosomal recessive inherited pseudoxanthoma elasticum (3)
-	-	2	not specified (2)
-	-	1	Arterial calcification, generalized, of infancy, 2 (1)
-	-	1	Pseudoxanthoma elasticum, forme fruste (1)
-	-	1	Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2;CN032334:Autosomal recessive inherited pseudoxanthoma elasticum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.89
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs58668703; hg19: chr16-16244584; COSMIC: COSV104567702;