12-21842326-C-T

Position:

• chr12-21842326-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_020297.4(ABCC9):​c.3461G>A​(p.Arg1154Gln) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1154W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC9 NM_020297.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.84

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]

ABCC9 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a topological_domain Extracellular (size 96) in uniprot entity ABCC9_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) 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 chr12-21842327-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ABCC9. . Gene score misZ 4.9694 (greater than the threshold 3.09). Trascript score misZ 7.023 (greater than threshold 3.09). GenCC has associacion of gene with hypertrichotic osteochondrodysplasia Cantu type, dilated cardiomyopathy, acromegaloid facial appearance syndrome, Brugada syndrome, atrial fibrillation, familial, 12, intellectual disability and myopathy syndrome, dilated cardiomyopathy 1O, familial isolated dilated cardiomyopathy, hypertrichosis-acromegaloid facial appearance syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 12-21842326-C-T is Pathogenic according to our data. Variant chr12-21842326-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 31947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21842326-C-T is described in Lovd as [Pathogenic]. Variant chr12-21842326-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC9	NM_020297.4	c.3461G>A	p.Arg1154Gln	missense_variant	29/40	ENST00000261200.9	NP_064693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9	c.3461G>A	p.Arg1154Gln	missense_variant	29/40	5	NM_020297.4	ENSP00000261200.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrichotic osteochondrodysplasia Cantu type Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	May 02, 2018	[ACMG/AMP: PS1, PS2, PS3, PM2, PP2, PP3] This alteration has an amino acid change previously established as pathogenic (regardless of nucleotide change) [PS1], is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is absent from or rarely observed in large-scale population databases [PM2], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3]. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 16, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 08, 2012	- -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2023	Published functional studies suggest a damaging effect via reduced ATP sensitivity of the potassium channel (Harakalova et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23307537, 31828977, 29275331, 32622958, 32371413, 34056838, 31785789, 33529173, 22610116, 22608503) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Dilated cardiomyopathy 1O Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 20, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1154 amino acid residue in ABCC9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22608503, 26871653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects ABCC9 function (PMID: 22610116). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 31947). This missense change has been observed in individual(s) with Cantu syndrome (PMID: 22608503, 23307537). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1154 of the ABCC9 protein (p.Arg1154Gln). -

ABCC9-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported as a heterozygous change in patients Cantu Syndrome (PMID: PMID: 22610116, 23307537, 22608503, 31828977, 32622958). The c.3461G>A (p.Arg1154Gln) variant is located in a mutational hotspot for pathogenic variations associated with Cantu Syndrome (PMID: 22608503). Different amino acid changes at the same residue (p.R1154W & p.R1154G) have been previously reported in individuals with Cantu Syndrome (PMID: 22608503, 31828977, 29275331). Experimental studies have shown that this non-synonymous change causes abnormal channel function (PMID: 22610116, 33529173). The c.3461G>A (p.Arg1154Gln) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.3461G>A (p.Arg1154Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a discordant effect on protein function. Based on the available evidence, the c.3461G>A (p.Arg1154Gln) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	.;.;D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.1	M;.;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Pathogenic	0.82
Sift	Benign	0.049	D;D;D
Sift4G	Uncertain	0.044	D;D;D
Polyphen		1.0	D;.;P
Vest4		0.68
MutPred		0.74		Loss of methylation at R1154 (P = 0.0629);.;Loss of methylation at R1154 (P = 0.0629);
MVP		0.94
MPC		1.8
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.78
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387907209; hg19: chr12-21995260; COSMIC: COSV53970846;