NM_020297.4:c.2631G>A

Variant names:

• chr12-21852380-C-T
• rs139408145
• NM_020297.4:c.2631G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_020297.4(ABCC9):​c.2631G>A​(p.Thr877Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,613,838 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T877T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0042 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (153 hom.)
• Consequence: ABCC9 NM_020297.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.443
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-21852380-C-T is Benign according to our data. Variant chr12-21852380-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.443 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0684 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.2631G>A	p.Thr877Thr	synonymous	Exon 23 of 40	NP_064693.2	O60706-2
	ABCC9	NM_001377273.1		c.2631G>A	p.Thr877Thr	synonymous	Exon 24 of 41	NP_001364202.1	O60706-2
	ABCC9	NM_005691.4		c.2631G>A	p.Thr877Thr	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.2631G>A	p.Thr877Thr	synonymous	Exon 23 of 40	ENSP00000261200.4	O60706-2
	ABCC9	ENST00000261201.10	TSL:5	c.2631G>A	p.Thr877Thr	synonymous	Exon 23 of 41	ENSP00000261201.4	O60706-1
	ABCC9	ENST00000879186.1		c.2631G>A	p.Thr877Thr	synonymous	Exon 22 of 39	ENSP00000549245.1

Frequencies

GnomAD3 genomes AF: 0.00417 AC: 634 AN: 152064 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00913

GnomAD2 exomes AF: 0.0123 AC: 3081 AN: 251104 AF XY: 0.00957

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0741

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0234

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00752

GnomAD4 exome AF: 0.00289 AC: 4226 AN: 1461656 Hom.: 153 Cov.: 34 AF XY: 0.00255 AC XY: 1852 AN XY: 727132

African (AFR) AF: 0.000568 AC: 19 AN: 33470

American (AMR) AF: 0.0704 AC: 3150 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0194 AC: 771 AN: 39670

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86254

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53322

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.0000683 AC: 76 AN: 1111948

Other (OTH) AF: 0.00325 AC: 196 AN: 60382

GnomAD4 genome AF: 0.00416 AC: 633 AN: 152182 Hom.: 13 Cov.: 32 AF XY: 0.00449 AC XY: 334 AN XY: 74404

African (AFR) AF: 0.00120 AC: 50 AN: 41524

American (AMR) AF: 0.0299 AC: 456 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0178 AC: 92 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68014

Other (OTH) AF: 0.00903 AC: 19 AN: 2104

Alfa AF: 0.000705 Hom.: 1

Bravo AF: 0.00794

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	5.7
DANN	Benign	0.83
PhyloP100		-0.44
Mutation Taster		=95/5	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: rs139408145; hg19: chr12-22005314; COSMIC: COSV53979157;