ABCC9 p.Ser144Arg

Variant names:

• chr12-21923833-T-G
• rs1321404773
• ENST00000326684.8:c.430A>C
• ABCC9 p.Ser144Arg

Your query was ambiguous. Multiple possible variants found:

• chr12-21923833-T-G
• chr12-21923831-G-T
• chr12-21923831-G-C
• chr12-21923831-GCT-ACG
• chr12-21923831-GCT-TCG
• chr12-21923831-GCT-CCG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000326684.8(ABCC9):​c.430A>C​(p.Ser144Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 548,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: ABCC9 ENST00000326684.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300
• Publications: 0 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)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06570235).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000326684.8. 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.406+2109A>C		intron	N/A	NP_064693.2	O60706-2
	ABCC9	NM_001377273.1		c.406+2109A>C		intron	N/A	NP_001364202.1	O60706-2
	ABCC9	NM_005691.4		c.406+2109A>C		intron	N/A	NP_005682.2	O60706-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC9	ENST00000326684.8	TSL:1	c.430A>C	p.Ser144Arg	missense	Exon 7 of 7	ENSP00000317518.4	Q8N4N7
	ABCC9	ENST00000261200.9	TSL:5 MANE Select	c.406+2109A>C		intron	N/A	ENSP00000261200.4	O60706-2
	ABCC9	ENST00000621589.2	TSL:5	c.430A>C	p.Ser144Arg	missense	Exon 6 of 6	ENSP00000480233.1	Q8N4N7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000739 AC: 1 AN: 135326 AF XY: 0.0000136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000415

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 1 AN: 548440 Hom.: 0 Cov.: 0 AF XY: 0.00000337 AC XY: 1 AN XY: 297012

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 15714

American (AMR) AF: 0.0000289 AC: 1 AN: 34580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19938

East Asian (EAS) AF: 0.00 AC: 0 AN: 31958

South Asian (SAS) AF: 0.00 AC: 0 AN: 62438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4060

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 315662

Other (OTH) AF: 0.00 AC: 0 AN: 30516

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.75
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.066	T
MetaSVM	Uncertain	-0.088	T
PhyloP100		-0.030
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.23	T
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1321404773; hg19: chr12-22076767;