rs58386780

Variant names:

• chr12-21915695-G-A
• rs58386780
• NM_020297.4:c.789C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020297.4(ABCC9):​c.789C>T​(p.Cys263Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,611,134 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 24)
  • Exomes 𝑓: 0.0017 (28 hom.)
• Consequence: ABCC9 NM_020297.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.467
• Publications: 6 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 12-21915695-G-A is Benign according to our data. Variant chr12-21915695-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.467 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0108 (1624/149736) while in subpopulation AFR AF = 0.0358 (1454/40660). AF 95% confidence interval is 0.0342. There are 28 homozygotes in GnomAd4. There are 782 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AD,AR,Unknown gene

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.789C>T	p.Cys263Cys	synonymous	Exon 7 of 40	NP_064693.2	O60706-2
	ABCC9	NM_001377273.1		c.789C>T	p.Cys263Cys	synonymous	Exon 8 of 41	NP_001364202.1	O60706-2
	ABCC9	NM_005691.4		c.789C>T	p.Cys263Cys	synonymous	Exon 7 of 41	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.789C>T	p.Cys263Cys	synonymous	Exon 7 of 40	ENSP00000261200.4	O60706-2
	ABCC9	ENST00000261201.10	TSL:5	c.789C>T	p.Cys263Cys	synonymous	Exon 7 of 41	ENSP00000261201.4	O60706-1
	ABCC9	ENST00000879186.1		c.789C>T	p.Cys263Cys	synonymous	Exon 6 of 39	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1619 AN: 149628 Hom.: 27 Cov.: 24

Gnomad AFR AF: 0.0357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000237

Gnomad OTH AF: 0.00682

GnomAD2 exomes AF: 0.00402 AC: 1009 AN: 250920 AF XY: 0.00319

Gnomad AFR exome AF: 0.0379

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.0252

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000406

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00166 AC: 2426 AN: 1461398 Hom.: 28 Cov.: 31 AF XY: 0.00155 AC XY: 1124 AN XY: 727016

African (AFR) AF: 0.0350 AC: 1172 AN: 33442

American (AMR) AF: 0.00237 AC: 106 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 683 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5758

European-Non Finnish (NFE) AF: 0.000180 AC: 200 AN: 1111718

Other (OTH) AF: 0.00406 AC: 245 AN: 60360

GnomAD4 genome AF: 0.0108 AC: 1624 AN: 149736 Hom.: 28 Cov.: 24 AF XY: 0.0107 AC XY: 782 AN XY: 72994

African (AFR) AF: 0.0358 AC: 1454 AN: 40660

American (AMR) AF: 0.00328 AC: 49 AN: 14954

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 88 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5058

South Asian (SAS) AF: 0.00 AC: 0 AN: 4722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10108

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.000237 AC: 16 AN: 67506

Other (OTH) AF: 0.00674 AC: 14 AN: 2076

Alfa AF: 0.00445 Hom.: 19

Bravo AF: 0.0125

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Dilated cardiomyopathy 1O (2)
-	-	2	not provided (2)
-	-	1	ABCC9-related disorder (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Hypertrichotic osteochondrodysplasia Cantu type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.8
DANN	Benign	0.64
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs58386780; hg19: chr12-22068629;