12-21913072-GAAAA-GAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005691.4(ABCC9):​c.817-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,289,664 control chromosomes in the GnomAD database, including 75 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 32)
  • Exomes 𝑓: 0.014 (53 hom.)
• Consequence: ABCC9 NM_005691.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-21913072-GA-G is Benign according to our data. Variant chr12-21913072-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0115 (1397/121022) while in subpopulation NFE AF = 0.0159 (883/55526). AF 95% confidence interval is 0.015. There are 22 homozygotes in GnomAd4. There are 642 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 Unknown,AD,AR gene

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.817-7delT		splice_region intron	N/A	NP_064693.2
	ABCC9	NM_001377273.1		c.817-7delT		splice_region intron	N/A	NP_001364202.1
	ABCC9	NM_005691.4		c.817-7delT		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.817-7delT		splice_region intron	N/A	ENSP00000261200.4
	ABCC9	ENST00000261201.10	TSL:5	c.817-7delT		splice_region intron	N/A	ENSP00000261201.4
	ABCC9	ENST00000879186.1		c.817-7delT		splice_region intron	N/A	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1397 AN: 120982 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00322

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0270

Gnomad EAS AF: 0.000468

Gnomad SAS AF: 0.00592

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.0208

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0165 AC: 2186 AN: 132398 AF XY: 0.0170

Gnomad AFR exome AF: 0.00482

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0415

Gnomad EAS exome AF: 0.00109

Gnomad FIN exome AF: 0.00482

Gnomad NFE exome AF: 0.0216

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0144 AC: 16825 AN: 1168642 Hom.: 53 Cov.: 31 AF XY: 0.0145 AC XY: 8378 AN XY: 579462

African (AFR) AF: 0.00226 AC: 56 AN: 24782

American (AMR) AF: 0.0103 AC: 271 AN: 26206

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 564 AN: 19362

East Asian (EAS) AF: 0.000131 AC: 4 AN: 30426

South Asian (SAS) AF: 0.00847 AC: 474 AN: 55966

European-Finnish (FIN) AF: 0.00521 AC: 202 AN: 38742

Middle Eastern (MID) AF: 0.0294 AC: 138 AN: 4688

European-Non Finnish (NFE) AF: 0.0156 AC: 14413 AN: 921252

Other (OTH) AF: 0.0149 AC: 703 AN: 47218

GnomAD4 genome AF: 0.0115 AC: 1397 AN: 121022 Hom.: 22 Cov.: 32 AF XY: 0.0110 AC XY: 642 AN XY: 58618

African (AFR) AF: 0.00322 AC: 105 AN: 32648

American (AMR) AF: 0.0106 AC: 127 AN: 11974

Ashkenazi Jewish (ASJ) AF: 0.0270 AC: 79 AN: 2930

East Asian (EAS) AF: 0.000469 AC: 2 AN: 4262

South Asian (SAS) AF: 0.00596 AC: 23 AN: 3862

European-Finnish (FIN) AF: 0.00349 AC: 25 AN: 7156

Middle Eastern (MID) AF: 0.0227 AC: 5 AN: 220

European-Non Finnish (NFE) AF: 0.0159 AC: 883 AN: 55526

Other (OTH) AF: 0.0109 AC: 18 AN: 1646

Alfa AF: 0.00647 Hom.: 0

Bravo AF: 0.00985

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Cardiomyopathy (1)
-	-	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;