12-21913072-GAAAA-GAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_020297.4(ABCC9):c.817-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,289,664 control chromosomes in the GnomAD database, including 75 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 22 hom., cov: 32)

Exomes 𝑓: 0.014 ( 53 hom. )

Consequence

ABCC9
NM_020297.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -2.02

Publications

0 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 -16 ACMG points.

BP6

Variant 12-21913072-GA-G is Benign according to our data. Variant chr12-21913072-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0115 (1397/121022) while in subpopulation NFE AF = 0.0159 (883/55526). AF 95% confidence interval is 0.015. There are 22 homozygotes in GnomAd4. There are 642 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 Unknown,AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC9	NM_020297.4 link	c.817-7delT		splice_region_variant, intron_variant	Intron 7 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.817-7delT		splice_region_variant, intron_variant	Intron 7 of 39	5	NM_020297.4	ENSP00000261200.4		O60706-2

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1397

AN:

120982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00322

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.0270

Gnomad EAS

AF:

0.000468

Gnomad SAS

AF:

0.00592

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.0208

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0165

AC:

2186

AN:

132398

AF XY:

0.0170

show subpopulations

Gnomad AFR exome

AF:

0.00482

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.0415

Gnomad EAS exome

AF:

0.00109

Gnomad FIN exome

AF:

0.00482

Gnomad NFE exome

AF:

0.0216

Gnomad OTH exome

AF:

0.0194

GnomAD4 exome

AF:

0.0144

AC:

16825

AN:

1168642

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

8378

AN XY:

579462

show subpopulations

African (AFR)

AF:

0.00226

AC:

AN:

24782

American (AMR)

AF:

0.0103

AC:

271

AN:

26206

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

564

AN:

19362

East Asian (EAS)

AF:

0.000131

AC:

AN:

30426

South Asian (SAS)

AF:

0.00847

AC:

474

AN:

55966

European-Finnish (FIN)

AF:

0.00521

AC:

202

AN:

38742

Middle Eastern (MID)

AF:

0.0294

AC:

138

AN:

4688

European-Non Finnish (NFE)

AF:

0.0156

AC:

14413

AN:

921252

Other (OTH)

AF:

0.0149

AC:

703

AN:

47218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

681

1362

2042

2723

3404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

542

1084

1626

2168

2710

<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:

0.0115

AC:

1397

AN:

121022

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

642

AN XY:

58618

show subpopulations

African (AFR)

AF:

0.00322

AC:

105

AN:

32648

American (AMR)

AF:

0.0106

AC:

127

AN:

11974

Ashkenazi Jewish (ASJ)

AF:

0.0270

AC:

AN:

2930

East Asian (EAS)

AF:

0.000469

AC:

AN:

4262

South Asian (SAS)

AF:

0.00596

AC:

AN:

3862

European-Finnish (FIN)

AF:

0.00349

AC:

AN:

7156

Middle Eastern (MID)

AF:

0.0227

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.0159

AC:

883

AN:

55526

Other (OTH)

AF:

0.0109

AC:

AN:

1646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

125

188

250

313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00647

Hom.:

Bravo

AF:

0.00985

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 24, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

817-7delT in intron 5 of ABCC9: -

Aug 13, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ABCC9 c.817-7delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.017 in 132398 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 660 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC9 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.817-7delT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics, Academic Medical Center

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Sep 09, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Dilated cardiomyopathy 1O

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Jul 26, 2017

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

-2.0

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