12-21910317-CAAA-CAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020297.4(ABCC9):c.1165-6del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (8117 hom., cov: 0)
  • Exomes 𝑓: 0.41 (7229 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC9 NM_020297.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.57

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 12-21910317-CA-C is Benign according to our data. Variant chr12-21910317-CA-C is described in ClinVar as [Likely_benign]. Clinvar id is 35626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21910317-CA-C is described in Lovd as [Benign]. Variant chr12-21910317-CA-C is described in Lovd as [Benign]. Variant chr12-21910317-CA-C is described in Lovd as [Likely_benign]. Variant chr12-21910317-CA-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4	c.1165-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261200.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC9	ENST00000261200.9	c.1165-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_020297.4	P4

Frequencies

GnomAD3 genomes AF: 0.410 AC: 48591 AN: 118384 Hom.: 8118 Cov.: 0

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.395

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.413 AC: 485446 AN: 1174580 Hom.: 7229 Cov.: 0 AF XY: 0.413 AC XY: 241281 AN XY: 584916

Gnomad4 AFR exome AF: 0.365

Gnomad4 AMR exome AF: 0.417

Gnomad4 ASJ exome AF: 0.362

Gnomad4 EAS exome AF: 0.365

Gnomad4 SAS exome AF: 0.378

Gnomad4 FIN exome AF: 0.421

Gnomad4 NFE exome AF: 0.420

Gnomad4 OTH exome AF: 0.402

GnomAD4 genome AF: 0.410 AC: 48591 AN: 118392 Hom.: 8117 Cov.: 0 AF XY: 0.411 AC XY: 23357 AN XY: 56846

Gnomad4 AFR AF: 0.347

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.309

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.383

Gnomad4 FIN AF: 0.458

Gnomad4 NFE AF: 0.449

Gnomad4 OTH AF: 0.393

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2019	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

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	GeneDx	Jun 12, 2018	- -

Hypertrichotic osteochondrodysplasia Cantu type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated cardiomyopathy 1O Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2019

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 12, 2017

- -

Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs35857705; hg19: chr12-22063251;