rs3759236

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-21915915-G-T
• chr12-21915915-G-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.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: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• dilated cardiomyopathy 1O

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• 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, NO_KNOWN Submitted by: ClinGen, 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

Sel.	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	O60706-2
	ABCC9	NM_001377273.1		c.574-5C>A		splice_region intron	N/A	NP_001364202.1	O60706-2
	ABCC9	NM_005691.4		c.574-5C>A		splice_region intron	N/A	NP_005682.2	O60706-1

Ensembl Transcripts

Sel.	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	O60706-2
	ABCC9	ENST00000261201.10	TSL:5	c.574-5C>A		splice_region intron	N/A	ENSP00000261201.4	O60706-1
	ABCC9	ENST00000879186.1		c.574-5C>A		splice_region intron	N/A	ENSP00000549245.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Dilated cardiomyopathy 1O (2)
-	-	2	Hypertrichotic osteochondrodysplasia Cantu type (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

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;