12-21910317-CAAA-CAAAA

Position:

• chr12-21910317-CAAA-CAAAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_020297.4(ABCC9):​c.1165-6_1165-5insT 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.027 (48 hom., cov: 0)
  • Exomes 𝑓: 0.047 (3 hom.)
• Consequence: ABCC9 NM_020297.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:9
• 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 -9 ACMG points.

• BP6: Variant 12-21910317-C-CA is Benign according to our data. Variant chr12-21910317-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45385.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2, Benign=2}.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4	c.1165-6_1165-5insT		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.1165-6_1165-5insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_020297.4	P4

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 3155 AN: 118514 Hom.: 47 Cov.: 0

Gnomad AFR AF: 0.0463

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0405

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.00652

Gnomad MID AF: 0.0741

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0327

GnomAD4 exome AF: 0.0468 AC: 57307 AN: 1224094 Hom.: 3 Cov.: 0 AF XY: 0.0470 AC XY: 28735 AN XY: 610738

Gnomad4 AFR exome AF: 0.0796

Gnomad4 AMR exome AF: 0.0411

Gnomad4 ASJ exome AF: 0.0768

Gnomad4 EAS exome AF: 0.0586

Gnomad4 SAS exome AF: 0.0677

Gnomad4 FIN exome AF: 0.0312

Gnomad4 NFE exome AF: 0.0435

Gnomad4 OTH exome AF: 0.0548

GnomAD4 genome AF: 0.0267 AC: 3160 AN: 118522 Hom.: 48 Cov.: 0 AF XY: 0.0272 AC XY: 1549 AN XY: 56914

Gnomad4 AFR AF: 0.0465

Gnomad4 AMR AF: 0.0290

Gnomad4 ASJ AF: 0.0405

Gnomad4 EAS AF: 0.0116

Gnomad4 SAS AF: 0.0255

Gnomad4 FIN AF: 0.00652

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 24, 2012	1165-6_1165-5insT in intron 07 of ABCC9: This variant is not expected to have cl inical significance because it is located outside the conserved +/- 1, 2 region of the splicing consensus sequence and as part of a poly T stretch. -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 03, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hypertrichotic osteochondrodysplasia Cantu type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Familial atrial fibrillation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, 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

Dec 31, 2019

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;