12-21806064-CAAA-CAA

Variant names:

• chr12-21806064-CA-C
• rs4148680
• NM_020297.4:c.4450-5delT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020297.4(ABCC9):​c.4450-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 997,342 control chromosomes in the GnomAD database, including 165 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 0.028 (131 hom., cov: 32)
  • Exomes 𝑓: 0.11 (34 hom.)
• Consequence: ABCC9 NM_020297.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.729

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]

LOC105369689 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 12-21806064-CA-C is Benign according to our data. Variant chr12-21806064-CA-C is described in ClinVar as [Likely_benign]. Clinvar id is 35634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21806064-CA-C is described in Lovd as [Benign]. Variant chr12-21806064-CA-C is described in Lovd as [Likely_benign]. Variant chr12-21806064-CA-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC9	NM_020297.4	c.4450-5delT		splice_region_variant, intron_variant	Intron 38 of 39	ENST00000261200.9	NP_064693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9	c.4450-5delT		splice_region_variant, intron_variant	Intron 38 of 39	5	NM_020297.4	ENSP00000261200.4

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 3894 AN: 140288 Hom.: 131 Cov.: 32

Gnomad AFR AF: 0.0880

Gnomad AMI AF: 0.00113

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.000602

Gnomad EAS AF: 0.000611

Gnomad SAS AF: 0.000667

Gnomad FIN AF: 0.00781

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.0231

GnomAD4 exome AF: 0.114 AC: 97432 AN: 856984 Hom.: 34 Cov.: 0 AF XY: 0.114 AC XY: 47782 AN XY: 420852

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.0279 AC: 3910 AN: 140358 Hom.: 131 Cov.: 32 AF XY: 0.0278 AC XY: 1890 AN XY: 67882

Gnomad4 AFR AF: 0.0882

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.000602

Gnomad4 EAS AF: 0.000817

Gnomad4 SAS AF: 0.00111

Gnomad4 FIN AF: 0.00781

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.0229

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 02, 2019

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

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:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Mar 26, 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

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Benign:1

May 08, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jun 29, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hypertrophic cardiomyopathy 2 Other:1

-

Institute of Human Genetics, University of Wuerzburg

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs4148680; hg19: chr12-21958998;