12-21910317-CAA-C

Position:

• chr12-21910317-CAA-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_020297.4(ABCC9):​c.1165-7_1165-6del 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 0.0242 in 1,344,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 0)
  • Exomes 𝑓: 0.026 (0 hom.)
• Consequence: ABCC9 NM_020297.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 1.57

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 -1 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0264 (32415/1225652) while in subpopulation AMR AF= 0.0448 (1428/31910). AF 95% confidence interval is 0.0428. There are 0 homozygotes in gnomad4_exome. There are 15980 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4	c.1165-7_1165-6del		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.1165-7_1165-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_020297.4	P4

Frequencies

GnomAD3 genomes AF: 0.000633 AC: 75 AN: 118542 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000612

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000586

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00103

Gnomad SAS AF: 0.000261

Gnomad FIN AF: 0.00258

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000483

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0264 AC: 32415 AN: 1225652 Hom.: 0 AF XY: 0.0261 AC XY: 15980 AN XY: 611716

Gnomad4 AFR exome AF: 0.0156

Gnomad4 AMR exome AF: 0.0448

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.0118

Gnomad4 SAS exome AF: 0.0261

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.0268

Gnomad4 OTH exome AF: 0.0248

GnomAD4 genome AF: 0.000633 AC: 75 AN: 118550 Hom.: 0 Cov.: 0 AF XY: 0.000685 AC XY: 39 AN XY: 56928

Gnomad4 AFR AF: 0.000611

Gnomad4 AMR AF: 0.000586

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00103

Gnomad4 SAS AF: 0.000263

Gnomad4 FIN AF: 0.00258

Gnomad4 NFE AF: 0.000483

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 31, 2017	- -

Hypertrichotic osteochondrodysplasia Cantu type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Familial atrial fibrillation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35857705; hg19: chr12-22063251;