rs1555523855

Variant names:

• chr16-16223409-G-T
• rs1555523855
• NM_001171.6:c.26C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001171.6(ABCC6):​c.26C>A​(p.Ala9Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A9V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.133
• Publications: 1 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: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• arterial calcification of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000262332 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17422995).

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.26C>A	p.Ala9Glu	missense	Exon 1 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.26C>A	p.Ala9Glu	missense	Exon 1 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.26C>A	p.Ala9Glu	missense	Exon 1 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.26C>A	p.Ala9Glu	missense	Exon 1 of 31	ENSP00000205557.7
	ABCC6	ENST00000575728.1	TSL:1	c.26C>A	p.Ala9Glu	missense	Exon 1 of 2	ENSP00000461686.1
	ABCC6	ENST00000909083.1		c.26C>A	p.Ala9Glu	missense	Exon 1 of 32	ENSP00000579142.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1293828 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 634798

African (AFR) AF: 0.00 AC: 0 AN: 27264

American (AMR) AF: 0.00 AC: 0 AN: 31186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23010

East Asian (EAS) AF: 0.00 AC: 0 AN: 34856

South Asian (SAS) AF: 0.00 AC: 0 AN: 73772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1013110

Other (OTH) AF: 0.00 AC: 0 AN: 54124

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive inherited pseudoxanthoma elasticum (1)
-	1	-	Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.8
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.49	N
PhyloP100		0.13
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.054
Sift	Benign	0.033	D
Sift4G	Uncertain	0.031	D
Polyphen		0.11	B
Vest4		0.092
MutPred		0.72		Gain of disorder (P = 0.0209)
MVP		0.51
MPC		1.5
ClinPred		0.37	T
GERP RS		-0.43
PromoterAI		-0.045	Neutral
Varity_R		0.12
gMVP		0.28
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs1555523855; hg19: chr16-16317266;