12-21910317-CAAAAA-CAAAAAA

Variant names:

• chr12-21910317-C-CA
• rs35857705
• NM_020297.4:c.1165-6dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_020297.4(ABCC9):​c.1165-6dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.027 (48 hom., cov: 0)
  • Exomes 𝑓: 0.047 (3 hom.)
• Consequence: ABCC9 NM_020297.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:9
• Conservation: PhyloP100: 1.57
• 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 -9 ACMG points.

• BP6: Variant 12-21910317-C-CA is Benign according to our data. Variant chr12-21910317-C-CA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45385.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0267 (3160/118522) while in subpopulation AFR AF = 0.0465 (1445/31094). AF 95% confidence interval is 0.0445. There are 48 homozygotes in GnomAd4. There are 1549 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 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.1165-6dupT		splice_region intron	N/A	NP_064693.2	O60706-2
	ABCC9	NM_001377273.1		c.1165-6dupT		splice_region intron	N/A	NP_001364202.1	O60706-2
	ABCC9	NM_005691.4		c.1165-6dupT		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.1165-6_1165-5insT		splice_region intron	N/A	ENSP00000261200.4	O60706-2
	ABCC9	ENST00000261201.10	TSL:5	c.1165-6_1165-5insT		splice_region intron	N/A	ENSP00000261201.4	O60706-1
	ABCC9	ENST00000879186.1		c.1165-6_1165-5insT		splice_region intron	N/A	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 3155 AN: 118514 Hom.: 47 Cov.: 0

Gnomad AFR AF: 0.0463

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0405

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.00652

Gnomad MID AF: 0.0741

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0327

GnomAD2 exomes AF: 0.0441 AC: 6257 AN: 142000 AF XY: 0.0446

Gnomad AFR exome AF: 0.0646

Gnomad AMR exome AF: 0.0372

Gnomad ASJ exome AF: 0.0772

Gnomad EAS exome AF: 0.0705

Gnomad FIN exome AF: 0.0233

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0517

GnomAD4 exome AF: 0.0468 AC: 57307 AN: 1224094 Hom.: 3 Cov.: 0 AF XY: 0.0470 AC XY: 28735 AN XY: 610738

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0796 AC: 2094 AN: 26294

American (AMR) AF: 0.0411 AC: 1327 AN: 32256

Ashkenazi Jewish (ASJ) AF: 0.0768 AC: 1672 AN: 21764

East Asian (EAS) AF: 0.0586 AC: 1973 AN: 33694

South Asian (SAS) AF: 0.0677 AC: 4707 AN: 69552

European-Finnish (FIN) AF: 0.0312 AC: 1174 AN: 37610

Middle Eastern (MID) AF: 0.0791 AC: 374 AN: 4726

European-Non Finnish (NFE) AF: 0.0435 AC: 41195 AN: 947284

Other (OTH) AF: 0.0548 AC: 2791 AN: 50914

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0267 AC: 3160 AN: 118522 Hom.: 48 Cov.: 0 AF XY: 0.0272 AC XY: 1549 AN XY: 56914

African (AFR) AF: 0.0465 AC: 1445 AN: 31094

American (AMR) AF: 0.0290 AC: 346 AN: 11948

Ashkenazi Jewish (ASJ) AF: 0.0405 AC: 112 AN: 2768

East Asian (EAS) AF: 0.0116 AC: 45 AN: 3884

South Asian (SAS) AF: 0.0255 AC: 97 AN: 3798

European-Finnish (FIN) AF: 0.00652 AC: 43 AN: 6592

Middle Eastern (MID) AF: 0.0773 AC: 15 AN: 194

European-Non Finnish (NFE) AF: 0.0160 AC: 896 AN: 55868

Other (OTH) AF: 0.0326 AC: 53 AN: 1628

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	1	2	not provided (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Dilated cardiomyopathy 1O (1)
-	1	-	Dilated Cardiomyopathy, Dominant (1)
-	1	-	Familial atrial fibrillation (1)
-	1	-	Hypertrichotic osteochondrodysplasia Cantu type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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: rs35857705; hg19: chr12-22063251; COSMIC: COSV53967822;