rs63750414

Positions:

• chr16-16154910-A-G
• chr16-16154910-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001171.6(ABCC6):​c.4004T>C​(p.Leu1335Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,534 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. L1335Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.31

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 5) in uniprot entity MRP6_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-16154910-A-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 16-16154910-A-G is Pathogenic according to our data. Variant chr16-16154910-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 433342.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-16154910-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.4004T>C	p.Leu1335Pro	missense_variant	28/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.3662T>C	p.Leu1221Pro	missense_variant	28/31		NP_001338729.1
ABCC6	NR_147784.1	n.3666T>C		non_coding_transcript_exon_variant	26/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.4004T>C	p.Leu1335Pro	missense_variant	28/31	1	NM_001171.6	ENSP00000205557	P1
ABCC6	ENST00000576204.6	n.867T>C		non_coding_transcript_exon_variant	1/2	5
ABCC6	ENST00000456970.6	c.*1013T>C		3_prime_UTR_variant, NMD_transcript_variant	26/29	2		ENSP00000405002
ABCC6	ENST00000622290.5	c.*176T>C		3_prime_UTR_variant, NMD_transcript_variant	29/32	5		ENSP00000483331

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458534 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725260

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.0	D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.95		Loss of stability (P = 0.0202);.;
MVP		0.94
MPC		0.51
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.94

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: rs63750414; hg19: chr16-16248767;