rs387907208

chr12-21842327-G-Achr12-21842327-G-C

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.3460C>T(p.Arg1154Trp) variant causes a missense change. 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. R1154Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC9 NM_020297.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 3.66

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 17 ACMG points.

• PM1: In a domain ABC transmembrane type-1 2 (size 280) in uniprot entity ABCC9_HUMAN there are 34 pathogenic changes around while only 9 benign (79%) 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 chr12-21842326-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.
• PP2: Missense variant where missense usually causes diseases, ABCC9
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant 12-21842327-G-A is Pathogenic according to our data. Variant chr12-21842327-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21842327-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4	c.3460C>T	p.Arg1154Trp	missense_variant	29/40	ENST00000261200.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC9	ENST00000261200.9	c.3460C>T	p.Arg1154Trp	missense_variant	29/40	5	NM_020297.4	P4
	ENST00000539874.1	n.331+11133G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461632 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrichotic osteochondrodysplasia Cantu type Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	research	Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute	Dec 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 30, 2019	The ABCC9 c.3640C>T (p.Arg1154Trp) variant is a missense variant that is located in the second transmembrane domain of ABCC9. This variant has been reported in a heterozygous de novo state in five unrelated individuals with Cantu syndrome (van Bon et al. 2012; Harakalova et al. 2012; Afifi et al. 2016). The p.Arg1154Trp variant is not reported in the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is a rare variant. Another missense change at the same residue, p.Arg1154Gln, has also been reported to be pathogenic for Cantu syndrome (van Bon et al. 2012; Harakalova et al. 2012). Based on the collective evidence and the application of the ACMG criteria, the p.Arg1154Trp variant is classified as pathogenic for Cantu syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 25, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 08, 2012	- -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26656175, 28690487, 27316244, 29275331, 31030551, 31828977, 34056838, 32065455, 25790160, 26871653, 22610116, 22608503) -

Dilated cardiomyopathy 1O Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 11, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1154 of the ABCC9 protein (p.Arg1154Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Cantu syndrome (PMID: 22608503, 22610116, 25790160, 26656175, 26871653). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 31946). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC9 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, 22610116, 23307537). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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 with Cantu syndrome (PMID: 22608503, 22610116, 25790160, 26871653, 26656175, 28690487, 31828977, 32065455, 34453476). The c.3460C>T (p.Arg1154Trp) 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.R1154G and p.R1154Q) have been previously reported in individuals with Cantu syndrome (PMID: 31828977, 32065455, 32371413, 32622958, 23307537). Experimental studies showed that this change caused abnormal potassium channel function (PMID: 22610116). The c.3460C>T (p.Arg1154Trp) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.3460C>T (p.Arg1154Trp) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3460C>T (p.Arg1154Trp) variant is classified as Pathogenic. -

Patent ductus arteriosus;C0025990:Micrognathia;C0149721:Left ventricular hypertrophy;C0240543:Bulbous nose;C0424503:Abnormal facial shape;C0426870:Large hands;C0426886:Tapered finger;C0678230:Epicanthus;C1836542:Depressed nasal bridge;C1842366:Low anterior hairline;C1844820:Joint hypermobility;C1845847:Coarse facial features;C1846423:Thick upper lip vermilion;C2243051:Macrocephaly;C4025871:Abnormality of the face Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Jun 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.2	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.022	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.79
MutPred		0.76		Loss of disorder (P = 0.0359);.;Loss of disorder (P = 0.0359);
MVP		0.96
MPC		1.7
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.90
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.31		Position offset: -13

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907208; hg19: chr12-21995261; COSMIC: COSV53963892;