NM_020297.4:c.2769+28A>C

Variant names:

• chr12-21852069-T-G
• rs2307024
• NM_020297.4:c.2769+28A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 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)

ENSG00000257022 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 261216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ABCC9	NM_020297.4	c.2769+28A>C		intron_variant	Intron 24 of 39	ENST00000261200.9	NP_064693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9	c.2769+28A>C		intron_variant	Intron 24 of 39	5	NM_020297.4	ENSP00000261200.4

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

GnomAD2 exomes AF: 0.384 AC: 95922 AN: 249670 AF XY: 0.395

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 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

African (AFR) AF: 0.246 AC: 8214 AN: 33430

American (AMR) AF: 0.317 AC: 14177 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 11111 AN: 26104

East Asian (EAS) AF: 0.273 AC: 10803 AN: 39596

South Asian (SAS) AF: 0.479 AC: 41235 AN: 86170

European-Finnish (FIN) AF: 0.383 AC: 20264 AN: 52954

Middle Eastern (MID) AF: 0.463 AC: 2651 AN: 5722

European-Non Finnish (NFE) AF: 0.415 AC: 460475 AN: 1110746

Other (OTH) AF: 0.407 AC: 24546 AN: 60276

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

African (AFR) AF: 0.250 AC: 10379 AN: 41522

American (AMR) AF: 0.328 AC: 5001 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1492 AN: 3468

East Asian (EAS) AF: 0.279 AC: 1445 AN: 5176

South Asian (SAS) AF: 0.479 AC: 2307 AN: 4820

European-Finnish (FIN) AF: 0.385 AC: 4056 AN: 10542

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27997 AN: 67952

Other (OTH) AF: 0.380 AC: 804 AN: 2114

Alfa AF: 0.387 Hom.: 21888

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrichotic osteochondrodysplasia Cantu type Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.3
DANN	Benign	0.70
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2307024; hg19: chr12-22005003; COSMIC: COSV107304710;