16-16198167-T-C

Variant names:

• chr16-16198167-T-C
• rs72653764
• NM_001171.6:c.1192A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM5 PP3_Moderate PP5

The NM_001171.6(ABCC6):​c.1192A>G​(p.Ser398Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000413 in 1,451,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S398R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.37
• Publications: 3 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-16198165-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433377.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 16-16198167-T-C is Pathogenic according to our data. Variant chr16-16198167-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 433225.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	NM_001171.6	MANE Select	c.1192A>G	p.Ser398Gly	missense	Exon 10 of 31	NP_001162.5
	ABCC6	NM_001440309.1		c.1192A>G	p.Ser398Gly	missense	Exon 10 of 31	NP_001427238.1
	ABCC6	NM_001440310.1		c.1192A>G	p.Ser398Gly	missense	Exon 10 of 30	NP_001427239.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC6	ENST00000205557.12	TSL:1 MANE Select	c.1192A>G	p.Ser398Gly	missense	Exon 10 of 31	ENSP00000205557.7
	ABCC6	ENST00000574094.6	TSL:5	c.1192A>G	p.Ser398Gly	missense	Exon 10 of 11	ENSP00000507301.1
	ABCC6	ENST00000456970.6	TSL:2	n.1192A>G		non_coding_transcript_exon	Exon 10 of 29	ENSP00000405002.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1451598 Hom.: 0 Cov.: 36 AF XY: 0.00000416 AC XY: 3 AN XY: 721190

African (AFR) AF: 0.00 AC: 0 AN: 33320

American (AMR) AF: 0.00 AC: 0 AN: 42884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25856

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.00 AC: 0 AN: 84784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000542 AC: 6 AN: 1107016

Other (OTH) AF: 0.00 AC: 0 AN: 59996

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1

Mar 01, 2021

PXE International

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.046	D
Polyphen		0.98	D
Vest4		0.77
MutPred		0.83		Gain of catalytic residue at S398 (P = 0.0198)
MVP		0.89
MPC		0.084
ClinPred		0.88	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.66
gMVP		0.42
Mutation Taster		=48/52	disease causing (ClinVar)

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: rs72653764; hg19: chr16-16292024;