12-21910317-CA-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020297.4(ABCC9):​c.1165-6delT 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (8117 hom., cov: 0)
  • Exomes 𝑓: 0.41 (7229 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC9 NM_020297.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• 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 -16 ACMG points.

• BP6: Variant 12-21910317-CA-C is Benign according to our data. Variant chr12-21910317-CA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.449 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.1165-6delT		splice_region intron	N/A	NP_064693.2	O60706-2
	ABCC9	NM_001377273.1		c.1165-6delT		splice_region intron	N/A	NP_001364202.1	O60706-2
	ABCC9	NM_005691.4		c.1165-6delT		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.1165-6delT		splice_region intron	N/A	ENSP00000261200.4	O60706-2
	ABCC9	ENST00000261201.10	TSL:5	c.1165-6delT		splice_region intron	N/A	ENSP00000261201.4	O60706-1
	ABCC9	ENST00000879186.1		c.1165-6delT		splice_region intron	N/A	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.410 AC: 48591 AN: 118384 Hom.: 8118 Cov.: 0

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.395

GnomAD2 exomes AF: 0.436 AC: 61855 AN: 142000 AF XY: 0.434

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.451

Gnomad ASJ exome AF: 0.403

Gnomad EAS exome AF: 0.389

Gnomad FIN exome AF: 0.453

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.437

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.413 AC: 485446 AN: 1174580 Hom.: 7229 Cov.: 0 AF XY: 0.413 AC XY: 241281 AN XY: 584916

African (AFR) AF: 0.365 AC: 9182 AN: 25140

American (AMR) AF: 0.417 AC: 12988 AN: 31146

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 7357 AN: 20296

East Asian (EAS) AF: 0.365 AC: 11239 AN: 30794

South Asian (SAS) AF: 0.378 AC: 25011 AN: 66132

European-Finnish (FIN) AF: 0.421 AC: 15177 AN: 36056

Middle Eastern (MID) AF: 0.346 AC: 1447 AN: 4188

European-Non Finnish (NFE) AF: 0.420 AC: 383469 AN: 912148

Other (OTH) AF: 0.402 AC: 19576 AN: 48680

GnomAD4 genome AF: 0.410 AC: 48591 AN: 118392 Hom.: 8117 Cov.: 0 AF XY: 0.411 AC XY: 23357 AN XY: 56846

African (AFR) AF: 0.347 AC: 10766 AN: 31066

American (AMR) AF: 0.459 AC: 5474 AN: 11928

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 854 AN: 2766

East Asian (EAS) AF: 0.253 AC: 983 AN: 3878

South Asian (SAS) AF: 0.383 AC: 1452 AN: 3796

European-Finnish (FIN) AF: 0.458 AC: 3022 AN: 6592

Middle Eastern (MID) AF: 0.299 AC: 58 AN: 194

European-Non Finnish (NFE) AF: 0.449 AC: 25025 AN: 55796

Other (OTH) AF: 0.393 AC: 639 AN: 1628

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs35857705; hg19: chr12-22063251;