16-16182910-T-C

Position:

• chr16-16182910-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000205557.12(ABCC6):​c.1964A>G​(p.Gln655Arg) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q655K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC6 ENST00000205557.12 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.41

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.

• PM1: In a domain ABC transporter 1 (size 224) in uniprot entity MRP6_HUMAN there are 59 pathogenic changes around while only 9 benign (87%) in ENST00000205557.12
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16093451).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.1964A>G	p.Gln655Arg	missense_variant	16/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.1622A>G	p.Gln541Arg	missense_variant	16/31		NP_001338729.1
ABCC6	NR_147784.1	n.2001A>G		non_coding_transcript_exon_variant	16/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.1964A>G	p.Gln655Arg	missense_variant	16/31	1	NM_001171.6	ENSP00000205557	P1
ABCC6	ENST00000622290.5	c.1964A>G	p.Gln655Arg	missense_variant, NMD_transcript_variant	16/32	5		ENSP00000483331
ABCC6	ENST00000456970.6	c.1964A>G	p.Gln655Arg	missense_variant, NMD_transcript_variant	16/29	2		ENSP00000405002

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1

Uncertain significance, no assertion criteria provided

research

PXE International

Feb 16, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	-0.61	N;N
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N;.
REVEL	Uncertain	0.36
Sift	Benign	0.23	T;.
Sift4G	Benign	0.59	T;T
Polyphen		0.0010	B;.
Vest4		0.13
MutPred		0.53		Gain of methylation at Q655 (P = 0.0294);Gain of methylation at Q655 (P = 0.0294);
MVP		0.76
MPC		0.072
ClinPred		0.15	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.32

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: rs72653779; hg19: chr16-16276767;