12-21910317-CAAAAA-CAAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

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

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

hypertrichotic osteochondrodysplasia Cantu type
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
dilated cardiomyopathy 1O
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
intellectual disability and myopathy syndrome
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
acromegaloid facial appearance syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypertrichosis-acromegaloid facial appearance syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Brugada syndrome
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
atrial fibrillation, familial, 12
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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 CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385. Variant chr12-21910317-C-CA is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 45385.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0267 (3160/118522) while in subpopulation AFR AF = 0.0465 (1445/31094). AF 95% confidence interval is 0.0445. There are 48 homozygotes in GnomAd4. There are 1549 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 Unknown,AD,AR gene

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0796

AC:

2094

AN:

26294

American (AMR)

AF:

0.0411

AC:

1327

AN:

32256

Ashkenazi Jewish (ASJ)

AF:

0.0768

AC:

1672

AN:

21764

East Asian (EAS)

AF:

0.0586

AC:

1973

AN:

33694

South Asian (SAS)

AF:

0.0677

AC:

4707

AN:

69552

European-Finnish (FIN)

AF:

0.0312

AC:

1174

AN:

37610

Middle Eastern (MID)

AF:

0.0791

AC:

374

AN:

4726

European-Non Finnish (NFE)

AF:

0.0435

AC:

41195

AN:

947284

Other (OTH)

AF:

0.0548

AC:

2791

AN:

50914

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

4654

9308

13962

18616

23270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.0465

AC:

1445

AN:

31094

American (AMR)

AF:

0.0290

AC:

346

AN:

11948

Ashkenazi Jewish (ASJ)

AF:

0.0405

AC:

112

AN:

2768

East Asian (EAS)

AF:

0.0116

AC:

AN:

3884

South Asian (SAS)

AF:

0.0255

AC:

AN:

3798

European-Finnish (FIN)

AF:

0.00652

AC:

AN:

6592

Middle Eastern (MID)

AF:

0.0773

AC:

AN:

194

European-Non Finnish (NFE)

AF:

0.0160

AC:

896

AN:

55868

Other (OTH)

AF:

0.0326

AC:

AN:

1628

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

139

278

418

557

696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

- -

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

- -

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

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

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

- -

Sep 03, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

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

PhyloP100

1.6

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over