rs72653786

chr16-16178961-A-Gchr16-16178961-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_001171.6(ABCC6):c.2252T>C(p.Met751Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M751K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC6 NM_001171.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.40

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 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr16-16178961-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433266.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC6	NM_001171.6	c.2252T>C	p.Met751Thr	missense_variant	18/31	ENST00000205557.12
ABCC6	NM_001351800.1	c.1910T>C	p.Met637Thr	missense_variant	18/31
ABCC6	NR_147784.1	n.2289T>C		non_coding_transcript_exon_variant	18/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12	c.2252T>C	p.Met751Thr	missense_variant	18/31	1	NM_001171.6	P1
ABCC6	ENST00000622290.5	c.2252T>C	p.Met751Thr	missense_variant, NMD_transcript_variant	18/32	5
ABCC6	ENST00000456970.6	c.2252T>C	p.Met751Thr	missense_variant, NMD_transcript_variant	18/29	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.
Eigen	Benign	-0.039
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.055	D
MutationAssessor	Benign	-0.78	N;N
MutationTaster	Benign	0.90	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;.
Sift4G	Benign	0.098	T;T
Polyphen		0.87	P;.
Vest4		0.38
MutPred		0.64		Loss of stability (P = 0.0761);Loss of stability (P = 0.0761);
MVP		0.83
MPC		0.11
ClinPred		0.83	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.52

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: rs72653786; hg19: chr16-16272818;