rs72653764

chr16-16198167-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 55) in uniprot entity MRP6_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_001171.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-16198165-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id 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 id is 433225.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-16198167-T-C is described in Lovd as [Pathogenic]. Variant chr16-16198167-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.1192A>G	p.Ser398Gly	missense_variant	10/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.850A>G	p.Ser284Gly	missense_variant	10/31
ABCC6	NR_147784.1	n.1229A>G		non_coding_transcript_exon_variant	10/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.1192A>G	p.Ser398Gly	missense_variant	10/31	1	NM_001171.6	P1
ABCC6	ENST00000574094.6	c.1192A>G	p.Ser398Gly	missense_variant	10/11	5
ABCC6	ENST00000622290.5	c.1192A>G	p.Ser398Gly	missense_variant, NMD_transcript_variant	10/32	5
ABCC6	ENST00000456970.6	c.1192A>G	p.Ser398Gly	missense_variant, NMD_transcript_variant	10/29	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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000542

Gnomad4 OTH exome AF: 0.00

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

Pathogenic, no assertion criteria provided

research

PXE International

Mar 01, 2021

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Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.046	D;D
Polyphen		0.98	D;.
Vest4		0.77
MutPred		0.83		Gain of catalytic residue at S398 (P = 0.0198);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs72653764; hg19: chr16-16292024;