rs774857795

chr12-21913069-GAAGAAAAAAAA-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_020297.4(ABCC9):c.817-14_817-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,512,556 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: ABCC9 NM_020297.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.928

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 12-21913069-GAAGAAAAAAAA-G is Benign according to our data. Variant chr12-21913069-GAAGAAAAAAAA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 416407.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000169 (232/1370438) while in subpopulation EAS AF= 0.00173 (62/35784). AF 95% confidence interval is 0.00139. There are 0 homozygotes in gnomad4_exome. There are 118 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4	c.817-14_817-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261200.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC9	ENST00000261200.9	c.817-14_817-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_020297.4	P4

Frequencies

GnomAD3 genomes AF: 0.000261 AC: 37 AN: 142034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000819

Gnomad SAS AF: 0.000221

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000921

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000169 AC: 232 AN: 1370438 Hom.: 0 AF XY: 0.000173 AC XY: 118 AN XY: 680746

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000669

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00173

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.0000536

GnomAD4 genome AF: 0.000260 AC: 37 AN: 142118 Hom.: 0 Cov.: 31 AF XY: 0.000290 AC XY: 20 AN XY: 68910

Gnomad4 AFR AF: 0.000285

Gnomad4 AMR AF: 0.00107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000821

Gnomad4 SAS AF: 0.000222

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000921

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000283

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 22, 2017

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 15, 2023

- -

Dilated cardiomyopathy 1O Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs774857795; hg19: chr12-22066003;