rs72653776

Variant names:

• chr16-16187210-G-A
• rs72653776
• NM_001171.6:c.1781C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3 PP5

The NM_001171.6(ABCC6):​c.1781C>T​(p.Ala594Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,460,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ABCC6 NM_001171.6 missense, splice_region
• Scores: Splicing: ADA: 0.04703
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.20

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 Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819
• PP5: Variant 16-16187210-G-A is Pathogenic according to our data. Variant chr16-16187210-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433519.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.1781C>T	p.Ala594Val	missense_variant, splice_region_variant	Exon 14 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.1439C>T	p.Ala480Val	missense_variant, splice_region_variant	Exon 14 of 31		NP_001338729.1
ABCC6	NR_147784.1	n.1818C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.1781C>T	p.Ala594Val	missense_variant, splice_region_variant	Exon 14 of 31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000456970.6	n.1781C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 29	2		ENSP00000405002.2
ABCC6	ENST00000622290.5	n.1781C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 32	5		ENSP00000483331.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248598 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460982 Hom.: 0 Cov.: 36 AF XY: 0.00000550 AC XY: 4 AN XY: 726762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely 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: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.66	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.017	D;.
Sift4G	Uncertain	0.037	D;D
Polyphen		0.98	D;.
Vest4		0.69
MutPred		0.82		Loss of catalytic residue at A594 (P = 0.1215);Loss of catalytic residue at A594 (P = 0.1215);
MVP		0.88
MPC		0.072
ClinPred		0.97	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.047
dbscSNV1_RF	Benign	0.32
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: rs72653776; hg19: chr16-16281067;