rs147895473

chr12-21842378-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020297.4(ABCC9):c.3409G>A(p.Val1137Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,614,012 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (17 hom.)
• Consequence: ABCC9 NM_020297.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.468

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 Benign. 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
• PP2: Missense variant where missense usually causes diseases, ABCC9
• BP4: Computational evidence support a benign effect (MetaRNN=0.0069136024).
• BP6: Variant 12-21842378-C-T is Benign according to our data. Variant chr12-21842378-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21842378-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0067 (1019/152158) while in subpopulation AFR AF= 0.0232 (962/41496). AF 95% confidence interval is 0.022. There are 14 homozygotes in gnomad4. There are 445 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4	c.3409G>A	p.Val1137Ile	missense_variant	29/40	ENST00000261200.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC9	ENST00000261200.9	c.3409G>A	p.Val1137Ile	missense_variant	29/40	5	NM_020297.4	P4
	ENST00000539874.1	n.331+11184C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 1014 AN: 152040 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00188 AC: 472 AN: 251320 Hom.: 9 AF XY: 0.00147 AC XY: 200 AN XY: 135824

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000739 AC: 1080 AN: 1461854 Hom.: 17 Cov.: 31 AF XY: 0.000685 AC XY: 498 AN XY: 727224

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00670 AC: 1019 AN: 152158 Hom.: 14 Cov.: 32 AF XY: 0.00598 AC XY: 445 AN XY: 74382

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00124 Hom.: 3

Bravo AF: 0.00766

ESP6500AA AF: 0.0241 AC: 106

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00222 AC: 270

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 04, 2018	The p.Val1137Ile variant in ABCC9 is classified as benign because it has been id entified in 2.4% (577/24024) of African American by the Genome Aggregation Datab ase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs147895473. ACMG/AMP Crite ria Applied: BA1. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dilated cardiomyopathy 1O Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	This variant is associated with the following publications: (PMID: 24439875) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -

Hypertrichotic osteochondrodysplasia Cantu type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 17, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	17
Dann	Benign	0.75
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.45	N;.;N
MutationTaster	Benign	0.80	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.20	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.60	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0020	B;.;B
Vest4		0.70
MVP		0.68
MPC		0.55
ClinPred		0.0020	T
GERP RS		3.4
Varity_R		0.036
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147895473; hg19: chr12-21995312;