12-21910317-CAAAAA-CAAAAAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_020297.4(ABCC9):​c.1165-7_1165-6dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00075 (0 hom.)
• Consequence: ABCC9 NM_020297.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• 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 -6 ACMG points.

• BP6: Variant 12-21910317-C-CAA is Benign according to our data. Variant chr12-21910317-C-CAA is described in ClinVar as Likely_benign. ClinVar VariationId is 3040132.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0015 (178/118584) while in subpopulation AFR AF = 0.00534 (166/31108). AF 95% confidence interval is 0.00467. There are 0 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 177 AN: 118576 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000335

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000522

Gnomad FIN AF: 0.000152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000716

Gnomad OTH AF: 0.000616

GnomAD2 exomes AF: 0.00196 AC: 279 AN: 142000 AF XY: 0.00170

Gnomad AFR exome AF: 0.00440

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00281

Gnomad EAS exome AF: 0.00250

Gnomad FIN exome AF: 0.000107

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00204

GnomAD4 exome AF: 0.000751 AC: 951 AN: 1267020 Hom.: 0 Cov.: 0 AF XY: 0.000830 AC XY: 525 AN XY: 632462

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

African (AFR) AF: 0.00413 AC: 113 AN: 27364

American (AMR) AF: 0.00155 AC: 51 AN: 32852

Ashkenazi Jewish (ASJ) AF: 0.00159 AC: 36 AN: 22680

East Asian (EAS) AF: 0.00101 AC: 36 AN: 35528

South Asian (SAS) AF: 0.00221 AC: 159 AN: 71972

European-Finnish (FIN) AF: 0.000311 AC: 12 AN: 38616

Middle Eastern (MID) AF: 0.00143 AC: 7 AN: 4906

European-Non Finnish (NFE) AF: 0.000504 AC: 494 AN: 980248

Other (OTH) AF: 0.000814 AC: 43 AN: 52854

⚠️ 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: 0.00150 AC: 178 AN: 118584 Hom.: 0 Cov.: 0 AF XY: 0.00146 AC XY: 83 AN XY: 56940

African (AFR) AF: 0.00534 AC: 166 AN: 31108

American (AMR) AF: 0.000335 AC: 4 AN: 11956

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3884

South Asian (SAS) AF: 0.000526 AC: 2 AN: 3802

European-Finnish (FIN) AF: 0.000152 AC: 1 AN: 6596

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

European-Non Finnish (NFE) AF: 0.0000716 AC: 4 AN: 55898

Other (OTH) AF: 0.000613 AC: 1 AN: 1630

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ABCC9-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=98/2	polymorphism

Splicing

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;