rs387907227

Positions:

• chr12-21842440-C-A
• chr12-21842440-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_020297.4(ABCC9):​c.3347G>T​(p.Arg1116Leu) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1116C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC9 NM_020297.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.87

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 71) in uniprot entity ABCC9_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_020297.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-21842441-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, ABCC9
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833
• PP5: Variant 12-21842440-C-A is Pathogenic according to our data. Variant chr12-21842440-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 387946.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4	c.3347G>T	p.Arg1116Leu	missense_variant	29/40	ENST00000261200.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC9	ENST00000261200.9	c.3347G>T	p.Arg1116Leu	missense_variant	29/40	5	NM_020297.4	P4
	ENST00000539874.1	n.331+11246C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2016

A variant that is likely pathogenic has been identified in the ABCC9 gene. While the R1116L variant has not been published as a pathogenic variant or reported as a benign variant, the R1116H and R1116C variants in the same residue have both been reported in patients with Cantu syndrome (Harakalova et al., 2012). The R1116H variant has been reported as a de novo variant in two additional patients with Cantu syndrome (Czeschik et al., 2013; Zhu et al., 2015). The R1116L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1116L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Finally, functional studies demonstrated that the R1116H variant in the same codon results in reduced ATP sensitivity (Harakalova et al., 2012).Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Benign	0.054
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	-0.063	T
MutationAssessor	Benign	1.1	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.74
Sift	Benign	0.099	T;T;T
Sift4G	Benign	0.11	T;T;D
Polyphen		0.081	B;.;B
Vest4		0.89
MutPred		0.68		Loss of disorder (P = 0.0801);.;Loss of disorder (P = 0.0801);
MVP		0.92
MPC		0.86
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.69
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs387907227; hg19: chr12-21995374;