NM_020297.4:c.2770-13A>G

Variant names:

• chr12-21848259-T-C
• rs184123387
• NM_020297.4:c.2770-13A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_020297.4(ABCC9):​c.2770-13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000461 in 1,608,738 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (3 hom.)
• Consequence: ABCC9 NM_020297.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: -0.464
• Publications: 2 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)

ENSG00000257022 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 12-21848259-T-C is Benign according to our data. Variant chr12-21848259-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162686.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000525 (80/152272) while in subpopulation NFE AF = 0.000456 (31/68028). AF 95% confidence interval is 0.000329. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 Unknown,AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC9	NM_020297.4	MANE Select	c.2770-13A>G		intron	N/A	NP_064693.2
	ABCC9	NM_001377273.1		c.2770-13A>G		intron	N/A	NP_001364202.1
	ABCC9	NM_005691.4		c.2770-13A>G		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.2770-13A>G		intron	N/A	ENSP00000261200.4
	ABCC9	ENST00000261201.10	TSL:5	c.2770-13A>G		intron	N/A	ENSP00000261201.4
	ABCC9	ENST00000879186.1		c.2770-13A>G		intron	N/A	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000681 AC: 171 AN: 250964 AF XY: 0.000678

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00361

Gnomad NFE exome AF: 0.000740

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000454 AC: 661 AN: 1456466 Hom.: 3 Cov.: 28 AF XY: 0.000461 AC XY: 334 AN XY: 724940

African (AFR) AF: 0.0000300 AC: 1 AN: 33336

American (AMR) AF: 0.0000672 AC: 3 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86154

European-Finnish (FIN) AF: 0.00319 AC: 170 AN: 53344

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5740

European-Non Finnish (NFE) AF: 0.000413 AC: 457 AN: 1107394

Other (OTH) AF: 0.000316 AC: 19 AN: 60168

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74454

African (AFR) AF: 0.0000481 AC: 2 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68028

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000295

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not specified (3)
-	1	1	Dilated cardiomyopathy 1O (2)
-	1	-	Hypertrichotic osteochondrodysplasia Cantu type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.055
DANN	Benign	0.51
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -1
DS_AL_spliceai		0.42		Position offset: -13

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

Other links and lift over

dbSNP: rs184123387; hg19: chr12-22001193;