chr12-21894157-C-T

Variant names:

• chr12-21894157-C-T
• rs76458291
• NM_020297.4:c.1677G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005691.4(ABCC9):​c.1677G>A​(p.Ala559Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,974 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: ABCC9 NM_005691.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -5.54
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-21894157-C-T is Benign according to our data. Variant chr12-21894157-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0018 (274/152224) while in subpopulation NFE AF = 0.00121 (82/68018). AF 95% confidence interval is 0.000995. There are 1 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.1677G>A	p.Ala559Ala	synonymous	Exon 14 of 40	NP_064693.2
	ABCC9	NM_001377273.1		c.1677G>A	p.Ala559Ala	synonymous	Exon 15 of 41	NP_001364202.1
	ABCC9	NM_005691.4		c.1677G>A	p.Ala559Ala	synonymous	Exon 14 of 41	NP_005682.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC9	ENST00000261200.9	TSL:5 MANE Select	c.1677G>A	p.Ala559Ala	synonymous	Exon 14 of 40	ENSP00000261200.4
	ABCC9	ENST00000261201.10	TSL:5	c.1677G>A	p.Ala559Ala	synonymous	Exon 14 of 41	ENSP00000261201.4
	ABCC9	ENST00000879186.1		c.1677G>A	p.Ala559Ala	synonymous	Exon 13 of 39	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 275 AN: 152106 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00228 AC: 572 AN: 251212 AF XY: 0.00224

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00127 AC: 1856 AN: 1461750 Hom.: 2 Cov.: 31 AF XY: 0.00121 AC XY: 881 AN XY: 727174

African (AFR) AF: 0.000896 AC: 30 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.0137 AC: 732 AN: 53412

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.000825 AC: 917 AN: 1111948

Other (OTH) AF: 0.00169 AC: 102 AN: 60380

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152224 Hom.: 1 Cov.: 32 AF XY: 0.00245 AC XY: 182 AN XY: 74412

African (AFR) AF: 0.000385 AC: 16 AN: 41542

American (AMR) AF: 0.000131 AC: 2 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0153 AC: 162 AN: 10590

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

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.000695

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Dilated cardiomyopathy 1O (2)
-	-	1	ABCC9-related disorder (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrichotic osteochondrodysplasia Cantu type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.12
DANN	Benign	0.32
PhyloP100		-5.5
Mutation Taster		=95/5	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: rs76458291; hg19: chr12-22047091;