rs150303433

Variant names:

• chr12-21818153-A-G
• rs150303433
• NM_020297.4:c.3768T>C

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.3768T>C​(p.Leu1256Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,606,382 control chromosomes in the GnomAD database, including 9 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 0.0020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0021 (9 hom.)
• Consequence: ABCC9 NM_020297.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: -0.514
• Publications: 6 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)

KCNJ8-AS1 (HGNC:58193):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-21818153-A-G is Benign according to our data. Variant chr12-21818153-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35633.
• BP7: Synonymous conserved (PhyloP=-0.514 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00201 (306/152216) while in subpopulation AMR AF = 0.00314 (48/15266). AF 95% confidence interval is 0.00261. There are 0 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.3768T>C	p.Leu1256Leu	synonymous	Exon 32 of 40	NP_064693.2	O60706-2
	ABCC9	NM_001377273.1		c.3768T>C	p.Leu1256Leu	synonymous	Exon 33 of 41	NP_001364202.1	O60706-2
	ABCC9	NM_005691.4		c.3768T>C	p.Leu1256Leu	synonymous	Exon 32 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.3768T>C	p.Leu1256Leu	synonymous	Exon 32 of 40	ENSP00000261200.4	O60706-2
	ABCC9	ENST00000261201.10	TSL:5	c.3768T>C	p.Leu1256Leu	synonymous	Exon 32 of 41	ENSP00000261201.4	O60706-1
	ABCC9	ENST00000879186.1		c.3768T>C	p.Leu1256Leu	synonymous	Exon 31 of 39	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 306 AN: 152098 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00209 AC: 526 AN: 251350 AF XY: 0.00194

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00575

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00299

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00208 AC: 3019 AN: 1454166 Hom.: 9 Cov.: 30 AF XY: 0.00211 AC XY: 1530 AN XY: 723978

African (AFR) AF: 0.000300 AC: 10 AN: 33326

American (AMR) AF: 0.00226 AC: 101 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 173 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86114

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53412

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5758

European-Non Finnish (NFE) AF: 0.00229 AC: 2532 AN: 1104992

Other (OTH) AF: 0.00186 AC: 112 AN: 60128

GnomAD4 genome AF: 0.00201 AC: 306 AN: 152216 Hom.: 0 Cov.: 30 AF XY: 0.00199 AC XY: 148 AN XY: 74422

African (AFR) AF: 0.000385 AC: 16 AN: 41560

American (AMR) AF: 0.00314 AC: 48 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00294 AC: 200 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00329 Hom.: 0

Bravo AF: 0.00226

EpiCase AF: 0.00300

EpiControl AF: 0.00362

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Cardiomyopathy (2)
-	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	-0.48
CADD	Benign	3.0
DANN	Benign	0.75
PhyloP100		-0.51
Mutation Taster		=99/1	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: rs150303433; hg19: chr12-21971087;