chr12-21806064-C-CA

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_020297.4(ABCC9):c.4450-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0858 in 1,073,430 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 Benign (★★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.099 ( 0 hom. )

Consequence

ABCC9
NM_020297.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.729

Publications

3 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:

KCNJ8-AS1 (HGNC:58193):

KCNJ8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP6

Variant 12-21806064-C-CA is Benign according to our data. Variant chr12-21806064-C-CA is described in ClinVar as Benign. ClinVar VariationId is 178859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC9	NM_020297.4 link	c.4450-5dupT		splice_region_variant, intron_variant	Intron 38 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.4450-5_4450-4insT		splice_region_variant, intron_variant	Intron 38 of 39	5	NM_020297.4	ENSP00000261200.4		O60706-2

Frequencies

GnomAD3 genomes

AF:

0.000925

AC:

130

AN:

140582

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000984

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00122

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000611

Gnomad SAS

AF:

0.00111

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.00336

Gnomad NFE

AF:

0.000624

Gnomad OTH

AF:

0.00157

GnomAD2 exomes

AF:

0.0949

AC:

7332

AN:

77272

AF XY:

0.0943

show subpopulations

Gnomad AFR exome

AF:

0.0553

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.110

Gnomad EAS exome

AF:

0.109

Gnomad FIN exome

AF:

0.123

Gnomad NFE exome

AF:

0.0789

Gnomad OTH exome

AF:

0.105

GnomAD4 exome

AF:

0.0986

AC:

92015

AN:

932776

Hom.:

Cov.:

AF XY:

0.0954

AC XY:

44216

AN XY:

463548

show subpopulations

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

African (AFR)

AF:

0.0848

AC:

1964

AN:

23158

American (AMR)

AF:

0.0696

AC:

2059

AN:

29574

Ashkenazi Jewish (ASJ)

AF:

0.0902

AC:

1501

AN:

16638

East Asian (EAS)

AF:

0.0971

AC:

2332

AN:

24022

South Asian (SAS)

AF:

0.0646

AC:

3730

AN:

57762

European-Finnish (FIN)

AF:

0.0810

AC:

2799

AN:

34566

Middle Eastern (MID)

AF:

0.0662

AC:

275

AN:

4156

European-Non Finnish (NFE)

AF:

0.104

AC:

73505

AN:

704242

Other (OTH)

AF:

0.0996

AC:

3850

AN:

38658

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

12962

25924

38885

51847

64809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

3040

6080

9120

12160

15200

<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:

0.000931

AC:

131

AN:

140654

Hom.:

Cov.:

AF XY:

0.000911

AC XY:

AN XY:

68034

show subpopulations

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

African (AFR)

AF:

0.000982

AC:

AN:

38712

American (AMR)

AF:

0.00122

AC:

AN:

13946

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3330

East Asian (EAS)

AF:

0.000613

AC:

AN:

4896

South Asian (SAS)

AF:

0.00111

AC:

AN:

4488

European-Finnish (FIN)

AF:

0.00283

AC:

AN:

8136

Middle Eastern (MID)

AF:

0.00362

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.000624

AC:

AN:

64060

Other (OTH)

AF:

0.00207

AC:

AN:

1928

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.390

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:

0.0509

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Apr 05, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1O

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

May 30, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.73

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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