NM_020297.4:c.406+38A>C

Variant names:

• chr12-21925904-T-G
• rs2277405
• NM_020297.4:c.406+38A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020297.4(ABCC9):​c.406+38A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 1,583,664 control chromosomes in the GnomAD database, including 303,770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32287 hom., cov: 31)
  • Exomes 𝑓: 0.61 (271483 hom.)
• Consequence: ABCC9 NM_020297.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.350
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-21925904-T-G is Benign according to our data. Variant chr12-21925904-T-G is described in ClinVar as Benign. ClinVar VariationId is 261217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

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.406+38A>C		intron	N/A	NP_064693.2
	ABCC9	NM_001377273.1		c.406+38A>C		intron	N/A	NP_001364202.1
	ABCC9	NM_005691.4		c.406+38A>C		intron	N/A	NP_005682.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC9	ENST00000261200.9	TSL:5 MANE Select	c.406+38A>C		intron	N/A	ENSP00000261200.4
	ABCC9	ENST00000326684.8	TSL:1	c.406+38A>C		intron	N/A	ENSP00000317518.4
	ABCC9	ENST00000684435.1		c.444A>C	p.Arg148Ser	missense	Exon 4 of 4	ENSP00000507779.1

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98441 AN: 151846 Hom.: 32249 Cov.: 31

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.749

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.683

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.607

Gnomad OTH AF: 0.667

GnomAD2 exomes AF: 0.638 AC: 159733 AN: 250198 AF XY: 0.644

Gnomad AFR exome AF: 0.708

Gnomad AMR exome AF: 0.564

Gnomad ASJ exome AF: 0.747

Gnomad EAS exome AF: 0.794

Gnomad FIN exome AF: 0.598

Gnomad NFE exome AF: 0.607

Gnomad OTH exome AF: 0.653

GnomAD4 exome AF: 0.613 AC: 877424 AN: 1431700 Hom.: 271483 Cov.: 30 AF XY: 0.617 AC XY: 440327 AN XY: 713742

African (AFR) AF: 0.707 AC: 23156 AN: 32738

American (AMR) AF: 0.568 AC: 25364 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 19502 AN: 25922

East Asian (EAS) AF: 0.779 AC: 30754 AN: 39494

South Asian (SAS) AF: 0.697 AC: 59431 AN: 85220

European-Finnish (FIN) AF: 0.596 AC: 31677 AN: 53158

Middle Eastern (MID) AF: 0.777 AC: 4345 AN: 5592

European-Non Finnish (NFE) AF: 0.594 AC: 644958 AN: 1085572

Other (OTH) AF: 0.644 AC: 38237 AN: 59388

GnomAD4 genome AF: 0.648 AC: 98535 AN: 151964 Hom.: 32287 Cov.: 31 AF XY: 0.650 AC XY: 48256 AN XY: 74264

African (AFR) AF: 0.711 AC: 29466 AN: 41472

American (AMR) AF: 0.605 AC: 9220 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.749 AC: 2602 AN: 3472

East Asian (EAS) AF: 0.799 AC: 4133 AN: 5170

South Asian (SAS) AF: 0.682 AC: 3287 AN: 4818

European-Finnish (FIN) AF: 0.603 AC: 6358 AN: 10546

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.607 AC: 41248 AN: 67940

Other (OTH) AF: 0.671 AC: 1414 AN: 2108

Alfa AF: 0.632 Hom.: 42210

Bravo AF: 0.652

Asia WGS AF: 0.714 AC: 2480 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hypertrichotic osteochondrodysplasia Cantu type (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.39
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

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: rs2277405; hg19: chr12-22078838; COSMIC: COSV107304718;