12-21913072-GAAA-GAA

Position:

• chr12-21913072-GAAA-GAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.02

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
ABCC9	NM_020297.4	c.817-7delT		splice_region_variant, intron_variant		ENST00000261200.9	NP_064693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9	c.817-7delT		splice_region_variant, intron_variant		5	NM_020297.4	ENSP00000261200.4

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1397 AN: 120982 Hom.: 22 Cov.: 32

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

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

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

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2012	817-7delT in intron 5 of ABCC9: -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2019	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. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Dilated cardiomyopathy 1O Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 26, 2017

- -

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: rs193922684; hg19: chr12-22066006;