12-21910317-CAAAAA-CAAA

Variant names:

• chr12-21910317-CAA-C
• rs35857705
• NM_020297.4:c.1165-7_1165-6delTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_020297.4(ABCC9):​c.1165-7_1165-6delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,344,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00063 (0 hom., cov: 0)
  • Exomes 𝑓: 0.026 (0 hom.)
• Consequence: ABCC9 NM_020297.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 12-21910317-CAA-C is Benign according to our data. Variant chr12-21910317-CAA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 308043.

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.1165-7_1165-6delTT		splice_region intron	N/A	NP_064693.2	O60706-2
	ABCC9	NM_001377273.1		c.1165-7_1165-6delTT		splice_region intron	N/A	NP_001364202.1	O60706-2
	ABCC9	NM_005691.4		c.1165-7_1165-6delTT		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.1165-7_1165-6delTT		splice_region intron	N/A	ENSP00000261200.4	O60706-2
	ABCC9	ENST00000261201.10	TSL:5	c.1165-7_1165-6delTT		splice_region intron	N/A	ENSP00000261201.4	O60706-1
	ABCC9	ENST00000879186.1		c.1165-7_1165-6delTT		splice_region intron	N/A	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.000633 AC: 75 AN: 118542 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000612

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000586

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00103

Gnomad SAS AF: 0.000261

Gnomad FIN AF: 0.00258

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000483

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0373 AC: 5300 AN: 142000 AF XY: 0.0366

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.0508

Gnomad ASJ exome AF: 0.0292

Gnomad EAS exome AF: 0.0184

Gnomad FIN exome AF: 0.0363

Gnomad NFE exome AF: 0.0395

Gnomad OTH exome AF: 0.0383

GnomAD4 exome AF: 0.0264 AC: 32415 AN: 1225652 Hom.: 0 AF XY: 0.0261 AC XY: 15980 AN XY: 611716

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

African (AFR) AF: 0.0156 AC: 417 AN: 26752

American (AMR) AF: 0.0448 AC: 1428 AN: 31910

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 379 AN: 22158

East Asian (EAS) AF: 0.0118 AC: 410 AN: 34610

South Asian (SAS) AF: 0.0261 AC: 1833 AN: 70260

European-Finnish (FIN) AF: 0.0348 AC: 1292 AN: 37084

Middle Eastern (MID) AF: 0.00751 AC: 36 AN: 4796

European-Non Finnish (NFE) AF: 0.0268 AC: 25350 AN: 946892

Other (OTH) AF: 0.0248 AC: 1270 AN: 51190

⚠️ 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: 0.000633 AC: 75 AN: 118550 Hom.: 0 Cov.: 0 AF XY: 0.000685 AC XY: 39 AN XY: 56928

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

African (AFR) AF: 0.000611 AC: 19 AN: 31104

American (AMR) AF: 0.000586 AC: 7 AN: 11954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2768

East Asian (EAS) AF: 0.00103 AC: 4 AN: 3880

South Asian (SAS) AF: 0.000263 AC: 1 AN: 3802

European-Finnish (FIN) AF: 0.00258 AC: 17 AN: 6596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 194

European-Non Finnish (NFE) AF: 0.000483 AC: 27 AN: 55874

Other (OTH) AF: 0.00 AC: 0 AN: 1630

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	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)		0.050		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;