NM_020297.4:c.3321C>T

Variant names:

• chr12-21842466-G-A
• rs35404804
• NM_020297.4:c.3321C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020297.4(ABCC9):​c.3321C>T​(p.Ile1107Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,613,962 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (29 hom.)
• Consequence: ABCC9 NM_020297.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.88
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• dilated cardiomyopathy 1O

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae), 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 12-21842466-G-A is Benign according to our data. Variant chr12-21842466-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.88 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1699/152256) while in subpopulation AFR AF = 0.039 (1620/41536). AF 95% confidence interval is 0.0374. There are 29 homozygotes in GnomAd4. There are 797 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 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.3321C>T	p.Ile1107Ile	synonymous	Exon 29 of 40	NP_064693.2
	ABCC9	NM_001377273.1		c.3321C>T	p.Ile1107Ile	synonymous	Exon 30 of 41	NP_001364202.1
	ABCC9	NM_005691.4		c.3321C>T	p.Ile1107Ile	synonymous	Exon 29 of 41	NP_005682.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC9	ENST00000261200.9	TSL:5 MANE Select	c.3321C>T	p.Ile1107Ile	synonymous	Exon 29 of 40	ENSP00000261200.4
	ABCC9	ENST00000261201.10	TSL:5	c.3321C>T	p.Ile1107Ile	synonymous	Exon 29 of 41	ENSP00000261201.4
	ABCC9	ENST00000879186.1		c.3321C>T	p.Ile1107Ile	synonymous	Exon 28 of 39	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1696 AN: 152140 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00304 AC: 763 AN: 251378 AF XY: 0.00210

Gnomad AFR exome AF: 0.0418

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00117 AC: 1704 AN: 1461706 Hom.: 29 Cov.: 31 AF XY: 0.000981 AC XY: 713 AN XY: 727164

African (AFR) AF: 0.0410 AC: 1371 AN: 33476

American (AMR) AF: 0.00210 AC: 94 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000729 AC: 81 AN: 1111872

Other (OTH) AF: 0.00252 AC: 152 AN: 60388

GnomAD4 genome AF: 0.0112 AC: 1699 AN: 152256 Hom.: 29 Cov.: 32 AF XY: 0.0107 AC XY: 797 AN XY: 74464

African (AFR) AF: 0.0390 AC: 1620 AN: 41536

American (AMR) AF: 0.00353 AC: 54 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68010

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00538 Hom.: 35

Bravo AF: 0.0131

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Cardiomyopathy (2)
-	-	2	Dilated cardiomyopathy 1O (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrichotic osteochondrodysplasia Cantu type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.6
DANN	Benign	0.72
PhyloP100		1.9
Mutation Taster		=98/2	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: rs35404804; hg19: chr12-21995400;