12-21806064-CAAA-CAAAAAAA

Variant names:

• chr12-21806064-C-CAAAA
• rs4148680
• NM_020297.4:c.4450-8_4450-5dupTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_020297.4(ABCC9):​c.4450-8_4450-5dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC9 NM_020297.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.729
• Publications: 0 publications found

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)

KCNJ8-AS1 (HGNC:58193):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC9	NM_020297.4	c.4450-8_4450-5dupTTTT		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.4450-5_4450-4insTTTT		splice_region_variant, intron_variant	Intron 38 of 39	5	NM_020297.4	ENSP00000261200.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 140826 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.36e-7 AC: 1 AN: 1195626 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 598560

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

African (AFR) AF: 0.00 AC: 0 AN: 28334

American (AMR) AF: 0.00 AC: 0 AN: 38236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22254

East Asian (EAS) AF: 0.00 AC: 0 AN: 33382

South Asian (SAS) AF: 0.00 AC: 0 AN: 75808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4964

European-Non Finnish (NFE) AF: 0.00000111 AC: 1 AN: 899140

Other (OTH) AF: 0.00 AC: 0 AN: 50146

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 140826 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 68074

African (AFR) AF: 0.00 AC: 0 AN: 38638

American (AMR) AF: 0.00 AC: 0 AN: 13954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3336

East Asian (EAS) AF: 0.00 AC: 0 AN: 4916

South Asian (SAS) AF: 0.00 AC: 0 AN: 4500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64164

Other (OTH) AF: 0.00 AC: 0 AN: 1912

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.73

Splicing

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

Other links and lift over

dbSNP: rs4148680; hg19: chr12-21958998;