16-16219655-C-T

Variant names:

• chr16-16219655-C-T
• rs879956688
• NM_001171.6:c.373G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001171.6(ABCC6):​c.373G>A​(p.Glu125Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000121 in 148,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.85
• Publications: 4 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

ENSG00000305554 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2716951).

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.373G>A	p.Glu125Lys	missense	Exon 4 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.373G>A	p.Glu125Lys	missense	Exon 4 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.373G>A	p.Glu125Lys	missense	Exon 4 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.373G>A	p.Glu125Lys	missense	Exon 4 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.373G>A	p.Glu125Lys	missense	Exon 4 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.373G>A	p.Glu125Lys	missense	Exon 4 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes AF: 0.000121 AC: 18 AN: 148680 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000673

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000297

Gnomad OTH AF: 0.000497

GnomAD2 exomes AF: 0.000776 AC: 44 AN: 56732 AF XY: 0.000593

Gnomad AFR exome AF: 0.00728

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000469

Gnomad OTH exome AF: 0.000514

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000139 AC: 19 AN: 1364296 Hom.: 0 Cov.: 25 AF XY: 0.0000104 AC XY: 7 AN XY: 675144

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000361 AC: 11 AN: 30500

American (AMR) AF: 0.00 AC: 0 AN: 35950

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25034

East Asian (EAS) AF: 0.00 AC: 0 AN: 36000

South Asian (SAS) AF: 0.0000254 AC: 2 AN: 78684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3998

European-Non Finnish (NFE) AF: 0.00000475 AC: 5 AN: 1053190

Other (OTH) AF: 0.00 AC: 0 AN: 56892

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000121 AC: 18 AN: 148788 Hom.: 0 Cov.: 25 AF XY: 0.0000967 AC XY: 7 AN XY: 72424

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000325 AC: 13 AN: 40048

American (AMR) AF: 0.0000672 AC: 1 AN: 14882

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5016

South Asian (SAS) AF: 0.00 AC: 0 AN: 4444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000297 AC: 2 AN: 67342

Other (OTH) AF: 0.000492 AC: 1 AN: 2032

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000148 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive inherited pseudoxanthoma elasticum (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
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.82		Gain of methylation at E125 (P = 0.0056)
MVP		0.66
MPC		1.5
ClinPred		0.078	T
GERP RS		4.4
Varity_R		0.30
gMVP		0.63
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs879956688; hg19: chr16-16313512;