12-21913072-GAAA-GAA

Variant summary

Our verdict is Benign. Variant got -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
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 45422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21913072-GA-G is described in Lovd as [Benign]. Variant chr12-21913072-GA-G is described in Lovd as [Likely_benign]. Variant chr12-21913072-GA-G is described in Lovd as [Benign].
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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCC9NM_020297.4 linkc.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
ABCC9ENST00000261200.9 linkc.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.:
22
Cov.:
32
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
GnomAD4 exome
AF:
0.0144
AC:
16825
AN:
1168642
Hom.:
53
Cov.:
31
AF XY:
0.0145
AC XY:
8378
AN XY:
579462
show subpopulations
Gnomad4 AFR exome
AF:
0.00226
Gnomad4 AMR exome
AF:
0.0103
Gnomad4 ASJ exome
AF:
0.0291
Gnomad4 EAS exome
AF:
0.000131
Gnomad4 SAS exome
AF:
0.00847
Gnomad4 FIN exome
AF:
0.00521
Gnomad4 NFE exome
AF:
0.0156
Gnomad4 OTH exome
AF:
0.0149
GnomAD4 genome
AF:
0.0115
AC:
1397
AN:
121022
Hom.:
22
Cov.:
32
AF XY:
0.0110
AC XY:
642
AN XY:
58618
show subpopulations
Gnomad4 AFR
AF:
0.00322
Gnomad4 AMR
AF:
0.0106
Gnomad4 ASJ
AF:
0.0270
Gnomad4 EAS
AF:
0.000469
Gnomad4 SAS
AF:
0.00596
Gnomad4 FIN
AF:
0.00349
Gnomad4 NFE
AF:
0.0159
Gnomad4 OTH
AF:
0.0109
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
-
Clinical Genetics, Academic Medical Center
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. -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
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

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
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

- -

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs193922684; hg19: chr12-22066006; API