rs387907211

chr12-21908099-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_020297.4(ABCC9):c.1433C>T(p.Ala478Val) variant causes a missense change involving the alteration of a 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC9 NM_020297.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.69

Genes affected

ABCC9 (HGNC:60): (ATP binding cassette subfamily C member 9) 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). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein is thought to form ATP-sensitive potassium channels in cardiac, skeletal, and vascular and non-vascular smooth muscle. Protein structure suggests a role as the drug-binding channel-modulating subunit of the extra-pancreatic ATP-sensitive potassium channels. Mutations in this gene are associated with cardiomyopathy dilated type 1O. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain ABC transmembrane type-1 1 (size 300) in uniprot entity ABCC9_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_020297.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ABCC9
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• PP5: Variant 12-21908099-G-A is Pathogenic according to our data. Variant chr12-21908099-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31949.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21908099-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4	c.1433C>T	p.Ala478Val	missense_variant	11/40	ENST00000261200.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC9	ENST00000261200.9	c.1433C>T	p.Ala478Val	missense_variant	11/40	5	NM_020297.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypertrichotic osteochondrodysplasia Cantu type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 08, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.7	D;N;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.95	P;.;B
Vest4		0.49
MutPred		0.55		Loss of disorder (P = 0.0577);.;Loss of disorder (P = 0.0577);
MVP		0.91
MPC		1.4
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.65
gMVP		0.93

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: rs387907211; hg19: chr12-22061033; COSMIC: COSV99686442;