12-21910317-CAAAAA-CAAA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_020297.4(ABCC9):c.1165-7_1165-6delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,344,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00063 ( 0 hom., cov: 0)

Exomes 𝑓: 0.026 ( 0 hom. )

Consequence

ABCC9
NM_020297.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

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: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 12-21910317-CAA-C is Benign according to our data. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043. Variant chr12-21910317-CAA-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 308043.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC9	NM_020297.4 link	c.1165-7_1165-6delTT		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.1165-7_1165-6delTT		splice_region_variant, intron_variant	Intron 9 of 39	5	NM_020297.4	ENSP00000261200.4		O60706-2

Frequencies

GnomAD3 genomes

AF:

0.000633

AC:

AN:

118542

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000612

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000586

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00103

Gnomad SAS

AF:

0.000261

Gnomad FIN

AF:

0.00258

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000483

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0373

AC:

5300

AN:

142000

AF XY:

0.0366

show subpopulations

Gnomad AFR exome

AF:

0.0227

Gnomad AMR exome

AF:

0.0508

Gnomad ASJ exome

AF:

0.0292

Gnomad EAS exome

AF:

0.0184

Gnomad FIN exome

AF:

0.0363

Gnomad NFE exome

AF:

0.0395

Gnomad OTH exome

AF:

0.0383

GnomAD4 exome

AF:

0.0264

AC:

32415

AN:

1225652

Hom.:

AF XY:

0.0261

AC XY:

15980

AN XY:

611716

show subpopulations

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

African (AFR)

AF:

0.0156

AC:

417

AN:

26752

American (AMR)

AF:

0.0448

AC:

1428

AN:

31910

Ashkenazi Jewish (ASJ)

AF:

0.0171

AC:

379

AN:

22158

East Asian (EAS)

AF:

0.0118

AC:

410

AN:

34610

South Asian (SAS)

AF:

0.0261

AC:

1833

AN:

70260

European-Finnish (FIN)

AF:

0.0348

AC:

1292

AN:

37084

Middle Eastern (MID)

AF:

0.00751

AC:

AN:

4796

European-Non Finnish (NFE)

AF:

0.0268

AC:

25350

AN:

946892

Other (OTH)

AF:

0.0248

AC:

1270

AN:

51190

⚠️ 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: 0.269

Heterozygous variant carriers

3268

6536

9803

13071

16339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

886

1772

2658

3544

4430

<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:

0.000633

AC:

AN:

118550

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

56928

show subpopulations

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

African (AFR)

AF:

0.000611

AC:

AN:

31104

American (AMR)

AF:

0.000586

AC:

AN:

11954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2768

East Asian (EAS)

AF:

0.00103

AC:

AN:

3880

South Asian (SAS)

AF:

0.000263

AC:

AN:

3802

European-Finnish (FIN)

AF:

0.00258

AC:

AN:

6596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

194

European-Non Finnish (NFE)

AF:

0.000483

AC:

AN:

55874

Other (OTH)

AF:

0.00

AC:

AN:

1630

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.374

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

May 31, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

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

- -

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)

0.050

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