12-21804904-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020297.4(ABCC9):c.4512+1094A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 152,318 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.033 (120 hom., cov: 32)
• Consequence: ABCC9 NM_020297.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.326

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-21804904-T-G is Benign according to our data. Variant chr12-21804904-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 681259.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0328 (4999/152318) while in subpopulation NFE AF= 0.0495 (3369/68018). AF 95% confidence interval is 0.0481. There are 120 homozygotes in gnomad4. There are 2356 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 120 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4	c.4512+1094A>C		intron_variant		ENST00000261200.9
LOC105369689	XR_007063241.1	n.632-22306T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC9	ENST00000261200.9	c.4512+1094A>C		intron_variant		5	NM_020297.4	P4

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4999 AN: 152200 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.00912

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0314

Gnomad ASJ AF: 0.0501

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.0427

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0496

Gnomad OTH AF: 0.0354

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0328 AC: 4999 AN: 152318 Hom.: 120 Cov.: 32 AF XY: 0.0316 AC XY: 2356 AN XY: 74484

Gnomad4 AFR AF: 0.00909

Gnomad4 AMR AF: 0.0314

Gnomad4 ASJ AF: 0.0501

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.0427

Gnomad4 NFE AF: 0.0495

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0454 Hom.: 184

Bravo AF: 0.0318

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	2.8
Dann	Benign	0.45

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17630922; hg19: chr12-21957838;