12-21910317-CAAAAA-CAAAAAAA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS1

The NM_020297.4(ABCC9):c.1165-7_1165-6dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00075 ( 0 hom. )

Consequence

ABCC9
NM_020297.4 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

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 -5 ACMG points.

BP6

Variant 12-21910317-C-CAA is Benign according to our data. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-21910317-C-CAA is described in CliVar as Likely_benign. Clinvar id is 3040132.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0015 (178/118584) while in subpopulation AFR AF = 0.00534 (166/31108). AF 95% confidence interval is 0.00467. There are 0 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

177

AN:

118576

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000335

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000522

Gnomad FIN

AF:

0.000152

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000716

Gnomad OTH

AF:

0.000616

GnomAD2 exomes

AF:

0.00196

AC:

279

AN:

142000

AF XY:

0.00170

show subpopulations

Gnomad AFR exome

AF:

0.00440

Gnomad AMR exome

AF:

0.00215

Gnomad ASJ exome

AF:

0.00281

Gnomad EAS exome

AF:

0.00250

Gnomad FIN exome

AF:

0.000107

Gnomad NFE exome

AF:

0.00155

Gnomad OTH exome

AF:

0.00204

GnomAD4 exome

AF:

0.000751

AC:

951

AN:

1267020

Hom.:

Cov.:

AF XY:

0.000830

AC XY:

525

AN XY:

632462

show subpopulations

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

African (AFR)

AF:

0.00413

AC:

113

AN:

27364

American (AMR)

AF:

0.00155

AC:

AN:

32852

Ashkenazi Jewish (ASJ)

AF:

0.00159

AC:

AN:

22680

East Asian (EAS)

AF:

0.00101

AC:

AN:

35528

South Asian (SAS)

AF:

0.00221

AC:

159

AN:

71972

European-Finnish (FIN)

AF:

0.000311

AC:

AN:

38616

Middle Eastern (MID)

AF:

0.00143

AC:

AN:

4906

European-Non Finnish (NFE)

AF:

0.000504

AC:

494

AN:

980248

Other (OTH)

AF:

0.000814

AC:

AN:

52854

⚠️ 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: 0.281

Heterozygous variant carriers

188

281

375

469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00150

AC:

178

AN:

118584

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

AN XY:

56940

show subpopulations

African (AFR)

AF:

0.00534

AC:

166

AN:

31108

American (AMR)

AF:

0.000335

AC:

AN:

11956

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2768

East Asian (EAS)

AF:

0.00

AC:

AN:

3884

South Asian (SAS)

AF:

0.000526

AC:

AN:

3802

European-Finnish (FIN)

AF:

0.000152

AC:

AN:

6596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

194

European-Non Finnish (NFE)

AF:

0.0000716

AC:

AN:

55898

Other (OTH)

AF:

0.000613

AC:

AN:

1630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

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: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ABCC9-related disorder

Benign:1

Mar 09, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=98/2

polymorphism

(source)

Splicing

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