chr16-16185001-G-A

Position:

• chr16-16185001-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001171.6(ABCC6):​c.1901C>T​(p.Ala634Val) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49

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 3 ACMG points.

• PM1: In a domain ABC transporter 1 (size 224) in uniprot entity MRP6_HUMAN there are 58 pathogenic changes around while only 9 benign (87%) in NM_001171.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2848176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.1901C>T	p.Ala634Val	missense_variant	15/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.1559C>T	p.Ala520Val	missense_variant	15/31
ABCC6	NR_147784.1	n.1938C>T		non_coding_transcript_exon_variant	15/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.1901C>T	p.Ala634Val	missense_variant	15/31	1	NM_001171.6	P1
ABCC6	ENST00000622290.5	c.1901C>T	p.Ala634Val	missense_variant, NMD_transcript_variant	15/32	5
ABCC6	ENST00000456970.6	c.1901C>T	p.Ala634Val	missense_variant, NMD_transcript_variant	15/29	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1

Uncertain significance, criteria provided, single submitter

research

PXE International

Feb 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	-0.060	N;N
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.015	D;T
Polyphen		0.68	P;.
Vest4		0.20
MutPred		0.58		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.78
MPC		0.072
ClinPred		0.92	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555513604; hg19: chr16-16278858;