rs2046345791

Variant names:

• chr16-16150156-C-A
• rs2046345791
• NM_001171.6:c.4489G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-16150156-C-A
• chr16-16150156-C-T

Variant summary

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

The NM_001171.6(ABCC6):​c.4489G>T​(p.Ala1497Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,630 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1497T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.82
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.4489G>T	p.Ala1497Ser	missense	Exon 31 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.4456G>T	p.Ala1486Ser	missense	Exon 31 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.4321G>T	p.Ala1441Ser	missense	Exon 30 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.4489G>T	p.Ala1497Ser	missense	Exon 31 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.4585G>T	p.Ala1529Ser	missense	Exon 32 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.4582G>T	p.Ala1528Ser	missense	Exon 32 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460630 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726618

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5078

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60296

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.8
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.21
MutPred		0.56		Gain of disorder (P = 0.0214)
MVP		0.76
MPC		0.37
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.63
gMVP		0.34
Mutation Taster		=62/38	polymorphism

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: rs2046345791; hg19: chr16-16244013;