rs144537241

Variant names:

• chr12-21852488-G-A
• rs144537241
• NM_020297.4:c.2523C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-21852488-G-A
• chr12-21852488-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_020297.4(ABCC9):​c.2523C>T​(p.Ala841Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,611,438 control chromosomes in the GnomAD database, including 30 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 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (28 hom.)
• Consequence: ABCC9 NM_020297.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: -0.530
• Publications: 4 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)

ENSG00000257022 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 12-21852488-G-A is Benign according to our data. Variant chr12-21852488-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35628.
• BP7: Synonymous conserved (PhyloP=-0.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00341 (519/152162) while in subpopulation NFE AF = 0.00575 (391/68006). AF 95% confidence interval is 0.00528. There are 2 homozygotes in GnomAd4. There are 229 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC9	NM_020297.4	MANE Select	c.2523C>T	p.Ala841Ala	synonymous	Exon 23 of 40	NP_064693.2	O60706-2
	ABCC9	NM_001377273.1		c.2523C>T	p.Ala841Ala	synonymous	Exon 24 of 41	NP_001364202.1	O60706-2
	ABCC9	NM_005691.4		c.2523C>T	p.Ala841Ala	synonymous	Exon 23 of 41	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.2523C>T	p.Ala841Ala	synonymous	Exon 23 of 40	ENSP00000261200.4	O60706-2
	ABCC9	ENST00000261201.10	TSL:5	c.2523C>T	p.Ala841Ala	synonymous	Exon 23 of 41	ENSP00000261201.4	O60706-1
	ABCC9	ENST00000879186.1		c.2523C>T	p.Ala841Ala	synonymous	Exon 22 of 39	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 519 AN: 152044 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00575

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00326 AC: 812 AN: 249336 AF XY: 0.00353

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.00547

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00491 AC: 7167 AN: 1459276 Hom.: 28 Cov.: 34 AF XY: 0.00480 AC XY: 3484 AN XY: 726026

African (AFR) AF: 0.000837 AC: 28 AN: 33470

American (AMR) AF: 0.000962 AC: 43 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00190 AC: 164 AN: 86256

European-Finnish (FIN) AF: 0.00171 AC: 87 AN: 50996

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5766

European-Non Finnish (NFE) AF: 0.00581 AC: 6462 AN: 1111904

Other (OTH) AF: 0.00477 AC: 288 AN: 60374

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152162 Hom.: 2 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74372

African (AFR) AF: 0.00152 AC: 63 AN: 41504

American (AMR) AF: 0.00118 AC: 18 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4818

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10584

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00575 AC: 391 AN: 68006

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00466 Hom.: 1

Bravo AF: 0.00335

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00622

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	1	1	Dilated cardiomyopathy 1O (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrichotic osteochondrodysplasia Cantu type (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.0
DANN	Benign	0.76
PhyloP100		-0.53
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs144537241; hg19: chr12-22005422;