NM_001171.6:c.373G>C

Variant names:

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

Variant summary

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

The NM_001171.6(ABCC6):​c.373G>C​(p.Glu125Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000293 in 1,364,486 control chromosomes in the GnomAD database, including 1 homozygotes. 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. E125K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000029 (1 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.85
• 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

ENSG00000305554 (HGNC:):

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.373G>C	p.Glu125Gln	missense	Exon 4 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.373G>C	p.Glu125Gln	missense	Exon 4 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.373G>C	p.Glu125Gln	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>C	p.Glu125Gln	missense	Exon 4 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.373G>C	p.Glu125Gln	missense	Exon 4 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.373G>C	p.Glu125Gln	missense	Exon 4 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000293 AC: 4 AN: 1364486 Hom.: 1 Cov.: 25 AF XY: 0.00000148 AC XY: 1 AN XY: 675212

African (AFR) AF: 0.00 AC: 0 AN: 30648

American (AMR) AF: 0.00 AC: 0 AN: 35958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25034

East Asian (EAS) AF: 0.00 AC: 0 AN: 36002

South Asian (SAS) AF: 0.0000381 AC: 3 AN: 78686

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

Middle Eastern (MID) AF: 0.000250 AC: 1 AN: 4000

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1053202

Other (OTH) AF: 0.00 AC: 0 AN: 56908

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.8
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.53		Loss of ubiquitination at K128 (P = 0.0593)
MVP		0.73
MPC		1.5
ClinPred		0.75	D
GERP RS		4.4
Varity_R		0.20
gMVP		0.45
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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;