12-21913072-GAAAA-GAAAAA

Variant names:

• chr12-21913072-G-GA
• rs193922684
• NM_020297.4:c.817-7dupT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_005691.4(ABCC9):​c.817-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,201,468 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.012 (0 hom.)
• Consequence: ABCC9 NM_005691.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.02
• Publications: 0 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dilated cardiomyopathy 1O

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 Submitted by: 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 -2 ACMG points.

• BP6: Variant 12-21913072-G-GA is Benign according to our data. Variant chr12-21913072-G-GA is described in ClinVar as Benign. ClinVar VariationId is 1164773.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005691.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC9	NM_020297.4	MANE Select	c.817-7dupT		splice_region intron	N/A	NP_064693.2
	ABCC9	NM_001377273.1		c.817-7dupT		splice_region intron	N/A	NP_001364202.1
	ABCC9	NM_005691.4		c.817-7dupT		splice_region intron	N/A	NP_005682.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC9	ENST00000261200.9	TSL:5 MANE Select	c.817-7_817-6insT		splice_region intron	N/A	ENSP00000261200.4
	ABCC9	ENST00000261201.10	TSL:5	c.817-7_817-6insT		splice_region intron	N/A	ENSP00000261201.4
	ABCC9	ENST00000879186.1		c.817-7_817-6insT		splice_region intron	N/A	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.0000744 AC: 9 AN: 120946 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000614

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000837

Gnomad ASJ AF: 0.000342

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000140

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000720

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0134 AC: 1771 AN: 132398 AF XY: 0.0131

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0263

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.0184

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.00966

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0121 AC: 13089 AN: 1080482 Hom.: 0 Cov.: 31 AF XY: 0.0115 AC XY: 6162 AN XY: 534836

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

African (AFR) AF: 0.0146 AC: 332 AN: 22784

American (AMR) AF: 0.0189 AC: 457 AN: 24198

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 232 AN: 17672

East Asian (EAS) AF: 0.00915 AC: 254 AN: 27760

South Asian (SAS) AF: 0.0164 AC: 826 AN: 50508

European-Finnish (FIN) AF: 0.0106 AC: 382 AN: 35936

Middle Eastern (MID) AF: 0.00542 AC: 24 AN: 4430

European-Non Finnish (NFE) AF: 0.0118 AC: 10080 AN: 853814

Other (OTH) AF: 0.0116 AC: 502 AN: 43380

⚠️ 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: 0.0000744 AC: 9 AN: 120986 Hom.: 0 Cov.: 32 AF XY: 0.0000853 AC XY: 5 AN XY: 58596

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

African (AFR) AF: 0.0000613 AC: 2 AN: 32644

American (AMR) AF: 0.0000835 AC: 1 AN: 11974

Ashkenazi Jewish (ASJ) AF: 0.000342 AC: 1 AN: 2928

East Asian (EAS) AF: 0.00 AC: 0 AN: 4260

South Asian (SAS) AF: 0.00 AC: 0 AN: 3858

European-Finnish (FIN) AF: 0.000140 AC: 1 AN: 7150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 220

European-Non Finnish (NFE) AF: 0.0000721 AC: 4 AN: 55508

Other (OTH) AF: 0.00 AC: 0 AN: 1646

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000486845), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0180 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated cardiomyopathy 1O (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0
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: rs193922684; hg19: chr12-22066006;