12-21915915-G-T

Variant names:

• chr12-21915915-G-T
• rs3759236
• NM_020297.4:c.574-5C>A

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.574-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 1,605,848 control chromosomes in the GnomAD database, including 286,598 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27476 hom., cov: 29)
  • Exomes 𝑓: 0.59 (259122 hom.)
• Consequence: ABCC9 NM_020297.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002551
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.499
• Publications: 19 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-21915915-G-T is Benign according to our data. Variant chr12-21915915-G-T is described in ClinVar as Benign. ClinVar VariationId is 45419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020297.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC9	NM_020297.4	MANE Select	c.574-5C>A		splice_region intron	N/A	NP_064693.2
	ABCC9	NM_001377273.1		c.574-5C>A		splice_region intron	N/A	NP_001364202.1
	ABCC9	NM_005691.4		c.574-5C>A		splice_region intron	N/A	NP_005682.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC9	ENST00000261200.9	TSL:5 MANE Select	c.574-5C>A		splice_region intron	N/A	ENSP00000261200.4
	ABCC9	ENST00000261201.10	TSL:5	c.574-5C>A		splice_region intron	N/A	ENSP00000261201.4
	ABCC9	ENST00000684084.1		c.574-5C>A		splice_region intron	N/A	ENSP00000507859.1

Frequencies

GnomAD3 genomes AF: 0.600 AC: 90862 AN: 151440 Hom.: 27456 Cov.: 29

Gnomad AFR AF: 0.585

Gnomad AMI AF: 0.517

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.714

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.613

GnomAD2 exomes AF: 0.610 AC: 151317 AN: 247920 AF XY: 0.615

Gnomad AFR exome AF: 0.581

Gnomad AMR exome AF: 0.544

Gnomad ASJ exome AF: 0.705

Gnomad EAS exome AF: 0.790

Gnomad FIN exome AF: 0.592

Gnomad NFE exome AF: 0.591

Gnomad OTH exome AF: 0.623

GnomAD4 exome AF: 0.594 AC: 864135 AN: 1454286 Hom.: 259122 Cov.: 33 AF XY: 0.597 AC XY: 432206 AN XY: 723728

African (AFR) AF: 0.576 AC: 19178 AN: 33286

American (AMR) AF: 0.546 AC: 24340 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 18506 AN: 26030

East Asian (EAS) AF: 0.775 AC: 30653 AN: 39572

South Asian (SAS) AF: 0.642 AC: 55184 AN: 85986

European-Finnish (FIN) AF: 0.591 AC: 31476 AN: 53302

Middle Eastern (MID) AF: 0.719 AC: 4113 AN: 5722

European-Non Finnish (NFE) AF: 0.582 AC: 643677 AN: 1105724

Other (OTH) AF: 0.616 AC: 37008 AN: 60104

GnomAD4 genome AF: 0.600 AC: 90934 AN: 151562 Hom.: 27476 Cov.: 29 AF XY: 0.602 AC XY: 44542 AN XY: 74006

African (AFR) AF: 0.585 AC: 24164 AN: 41314

American (AMR) AF: 0.571 AC: 8698 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 2441 AN: 3466

East Asian (EAS) AF: 0.795 AC: 4055 AN: 5098

South Asian (SAS) AF: 0.634 AC: 3035 AN: 4786

European-Finnish (FIN) AF: 0.598 AC: 6278 AN: 10502

Middle Eastern (MID) AF: 0.710 AC: 206 AN: 290

European-Non Finnish (NFE) AF: 0.594 AC: 40297 AN: 67884

Other (OTH) AF: 0.617 AC: 1296 AN: 2102

Alfa AF: 0.603 Hom.: 54075

Bravo AF: 0.596

Asia WGS AF: 0.673 AC: 2335 AN: 3478

EpiCase AF: 0.609

EpiControl AF: 0.607

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Jan 08, 2014

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.

Jul 19, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dilated cardiomyopathy 1O Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrichotic osteochondrodysplasia Cantu type Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Cardiovascular phenotype Benign:1

Mar 11, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.4
DANN	Benign	0.50
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -32

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

Other links and lift over

dbSNP: rs3759236; hg19: chr12-22068849; COSMIC: COSV107304714; COSMIC: COSV107304714;