NM_001171.6:c.4501G>A

Variant names:

• chr16-16150144-C-T
• rs63750874
• NM_001171.6:c.4501G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001171.6(ABCC6):​c.4501G>A​(p.Gly1501Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.64
• Publications: 2 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, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 16-16150144-C-T is Pathogenic according to our data. Variant chr16-16150144-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433368.Status of the report is criteria_provided_single_submitter, 1 stars.

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.4501G>A	p.Gly1501Ser	missense	Exon 31 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.4468G>A	p.Gly1490Ser	missense	Exon 31 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.4333G>A	p.Gly1445Ser	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.4501G>A	p.Gly1501Ser	missense	Exon 31 of 31	ENSP00000205557.7	O95255-1
	ABCC6	ENST00000909083.1		c.4597G>A	p.Gly1533Ser	missense	Exon 32 of 32	ENSP00000579142.1
	ABCC6	ENST00000909090.1		c.4594G>A	p.Gly1532Ser	missense	Exon 32 of 32	ENSP00000579149.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive inherited pseudoxanthoma elasticum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.8	L
PhyloP100		4.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.80		Loss of glycosylation at S1500 (P = 0.0652)
MVP		0.90
MPC		0.34
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.61
gMVP		0.62
Mutation Taster		=17/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63750874; hg19: chr16-16244001;