chr16-16165761-G-T

Variant names:

• chr16-16165761-G-T
• rs72657694
• NM_001171.6:c.3168C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001171.6(ABCC6):​c.3168C>A​(p.Asp1056Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (no stars). Synonymous variant affecting the same amino acid position (i.e. D1056D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.724

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 9 ACMG points.

• PM1: In a domain ABC transmembrane type-1 2 (size 281) in uniprot entity MRP6_HUMAN there are 30 pathogenic changes around while only 5 benign (86%) in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 16-16165761-G-T is Pathogenic according to our data. Variant chr16-16165761-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433303.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-16165761-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.3168C>A	p.Asp1056Glu	missense_variant	Exon 23 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.2826C>A	p.Asp942Glu	missense_variant	Exon 23 of 31		NP_001338729.1
ABCC6	NR_147784.1	n.3030C>A		non_coding_transcript_exon_variant	Exon 22 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.3168C>A	p.Asp1056Glu	missense_variant	Exon 23 of 31	1	NM_001171.6	ENSP00000205557.7
ABCC6	ENST00000456970.6	n.*377C>A		non_coding_transcript_exon_variant	Exon 22 of 29	2		ENSP00000405002.2
ABCC6	ENST00000622290.5	n.3168C>A		non_coding_transcript_exon_variant	Exon 23 of 32	5		ENSP00000483331.2
ABCC6	ENST00000456970.6	n.*377C>A		3_prime_UTR_variant	Exon 22 of 29	2		ENSP00000405002.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	0.26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.77	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.7	H;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.94		Gain of disorder (P = 0.1573);.;
MVP		0.64
MPC		0.38
ClinPred		0.98	D
GERP RS		-9.2
Varity_R		0.86
gMVP		0.67

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: rs72657694; hg19: chr16-16259618;