16-16219655-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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

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 Likely_benign. Variant got -1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.373G>A	p.Glu125Lys	missense_variant	Exon 4 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.31G>A	p.Glu11Lys	missense_variant	Exon 4 of 31		NP_001338729.1
ABCC6	NR_147784.1	n.410G>A		non_coding_transcript_exon_variant	Exon 4 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.373G>A	p.Glu125Lys	missense_variant	Exon 4 of 31	1	NM_001171.6	ENSP00000205557.7

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

GnomAD3 exomes AF: 0.000776 AC: 44 AN: 56732 Hom.: 0 AF XY: 0.000593 AC XY: 17 AN XY: 28666

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 SAS exome AF: 0.000306

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

Gnomad4 AFR exome AF: 0.000361

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000399

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000254

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.000325

Gnomad4 AMR AF: 0.0000672

Gnomad4 ASJ AF: 0.000290

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000297

Gnomad4 OTH AF: 0.000492

Alfa AF: 0.000148 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1

Feb 16, 2021

PXE International

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

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

Nov 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.82		Gain of methylation at E125 (P = 0.0056);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs879956688; hg19: chr16-16313512;