12-21910317-CAAA-CAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_020297.4(ABCC9):c.1165-6dupT variant causes a splice region, 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, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:9

Conservation

PhyloP100: 1.57

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ABCC9	NM_020297.4 link	c.1165-6dupT		splice_region_variant, intron_variant	Intron 9 of 39	ENST00000261200.9	NP_064693.2	O60706-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9 link	c.1165-6_1165-5insT		splice_region_variant, intron_variant	Intron 9 of 39	5	NM_020297.4	ENSP00000261200.4		O60706-2

Frequencies

GnomAD3 genomes

AF:

0.0266

AC:

3155

AN:

118514

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0441

AC:

6257

AN:

142000

AF XY:

0.0446

show subpopulations

Gnomad AFR exome

AF:

0.0646

Gnomad AMR exome

AF:

0.0372

Gnomad ASJ exome

AF:

0.0772

Gnomad EAS exome

AF:

0.0705

Gnomad FIN exome

AF:

0.0233

Gnomad NFE exome

AF:

0.0365

Gnomad OTH exome

AF:

0.0517

GnomAD4 exome

AF:

0.0468

AC:

57307

AN:

1224094

Hom.:

Cov.:

AF XY:

0.0470

AC XY:

28735

AN XY:

610738

show subpopulations

Gnomad4 AFR exome

AF:

0.0796

AC:

2094

AN:

26294

Gnomad4 AMR exome

AF:

0.0411

AC:

1327

AN:

32256

Gnomad4 ASJ exome

AF:

0.0768

AC:

1672

AN:

21764

Gnomad4 EAS exome

AF:

0.0586

AC:

1973

AN:

33694

Gnomad4 SAS exome

AF:

0.0677

AC:

4707

AN:

69552

Gnomad4 FIN exome

AF:

0.0312

AC:

1174

AN:

37610

Gnomad4 NFE exome

AF:

0.0435

AC:

41195

AN:

947284

Gnomad4 Remaining exome

AF:

0.0548

AC:

2791

AN:

50914

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

4654

9308

13962

18616

23270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

1616

3232

4848

6464

8080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0267

AC:

3160

AN:

118522

Hom.:

Cov.:

AF XY:

0.0272

AC XY:

1549

AN XY:

56914

show subpopulations

Gnomad4 AFR

AF:

0.0465

AC:

0.046472

AN:

0.046472

Gnomad4 AMR

AF:

0.0290

AC:

0.0289588

AN:

0.0289588

Gnomad4 ASJ

AF:

0.0405

AC:

0.0404624

AN:

0.0404624

Gnomad4 EAS

AF:

0.0116

AC:

0.011586

AN:

0.011586

Gnomad4 SAS

AF:

0.0255

AC:

0.0255398

AN:

0.0255398

Gnomad4 FIN

AF:

0.00652

AC:

0.00652306

AN:

0.00652306

Gnomad4 NFE

AF:

0.0160

AC:

0.0160378

AN:

0.0160378

Gnomad4 OTH

AF:

0.0326

AC:

0.0325553

AN:

0.0325553

Heterozygous variant carriers

139

278

418

557

696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 24, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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:1Benign:2

Sep 03, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 11, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrichotic osteochondrodysplasia Cantu type

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial atrial fibrillation

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated Cardiomyopathy, Dominant

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1O

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Mar 19, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=100/0

polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over