12-21852069-T-G

Position:

• chr12-21852069-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020297.4(ABCC9):​c.2769+28A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,611,748 control chromosomes in the GnomAD database, including 132,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10165 hom., cov: 32)
  • Exomes 𝑓: 0.41 (122301 hom.)
• Consequence: ABCC9 NM_020297.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.335

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-21852069-T-G is Benign according to our data. Variant chr12-21852069-T-G is described in ClinVar as [Benign]. Clinvar id is 261216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21852069-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC9	NM_020297.4	c.2769+28A>C		intron_variant		ENST00000261200.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC9	ENST00000261200.9	c.2769+28A>C		intron_variant		5	NM_020297.4	P4
	ENST00000539874.1	n.332-17513T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53920 AN: 151948 Hom.: 10152 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.380

GnomAD3 exomes AF: 0.384 AC: 95922 AN: 249670 Hom.: 19033 AF XY: 0.395 AC XY: 53356 AN XY: 134956

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.428

Gnomad EAS exome AF: 0.275

Gnomad SAS exome AF: 0.482

Gnomad FIN exome AF: 0.381

Gnomad NFE exome AF: 0.413

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.407 AC: 593476 AN: 1459682 Hom.: 122301 Cov.: 35 AF XY: 0.410 AC XY: 297608 AN XY: 726144

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.317

Gnomad4 ASJ exome AF: 0.426

Gnomad4 EAS exome AF: 0.273

Gnomad4 SAS exome AF: 0.479

Gnomad4 FIN exome AF: 0.383

Gnomad4 NFE exome AF: 0.415

Gnomad4 OTH exome AF: 0.407

GnomAD4 genome AF: 0.355 AC: 53971 AN: 152066 Hom.: 10165 Cov.: 32 AF XY: 0.355 AC XY: 26416 AN XY: 74330

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.380

Alfa AF: 0.396 Hom.: 16803

Bravo AF: 0.345

Asia WGS AF: 0.370 AC: 1285 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hypertrichotic osteochondrodysplasia Cantu type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.3
DANN	Benign	0.70

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: rs2307024; hg19: chr12-22005003;