chr16-16214329-G-C

Variant names:

• chr16-16214329-G-C
• rs1474063386
• NM_001171.6:c.595C>G

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.595C>G​(p.Gln199Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. Q199K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08055702).

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.595C>G	p.Gln199Glu	missense	Exon 5 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.595C>G	p.Gln199Glu	missense	Exon 5 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.595C>G	p.Gln199Glu	missense	Exon 5 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.595C>G	p.Gln199Glu	missense	Exon 5 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.595C>G	p.Gln199Glu	missense	Exon 5 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.595C>G	p.Gln199Glu	missense	Exon 5 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398706 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 689778

African (AFR) AF: 0.00 AC: 0 AN: 31586

American (AMR) AF: 0.00 AC: 0 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35722

South Asian (SAS) AF: 0.00 AC: 0 AN: 79226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078368

Other (OTH) AF: 0.00 AC: 0 AN: 57974

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	0.0013	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	5.0
DANN	Benign	0.90
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.85	L
PhyloP100		1.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.70	N
REVEL	Benign	0.27
Sift	Benign	0.53	T
Sift4G	Benign	0.84	T
Polyphen		0.0030	B
Vest4		0.084
MutPred		0.22		Gain of phosphorylation at S200 (P = 0.1326)
MVP		0.72
MPC		1.4
ClinPred		0.047	T
GERP RS		2.8
Varity_R		0.038
gMVP		0.11
Mutation Taster		=82/18	polymorphism

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: rs1474063386; hg19: chr16-16308186;