12-21805233-G-T

Position:

• chr12-21805233-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005691.4(ABCC9):​c.4591C>A​(p.Pro1531Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCC9 NM_005691.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13

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]

LOC105369689 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ABCC9. . Gene score misZ: 4.9694 (greater than the threshold 3.09). Trascript score misZ: 6.7938 (greater than threshold 3.09). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. GenCC has associacion of the gene with hypertrichotic osteochondrodysplasia Cantu type, dilated cardiomyopathy, acromegaloid facial appearance syndrome, Brugada syndrome, atrial fibrillation, familial, 12, intellectual disability and myopathy syndrome, dilated cardiomyopathy 1O, familial isolated dilated cardiomyopathy, hypertrichosis-acromegaloid facial appearance syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1929059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC9	NM_020297.4	c.4512+765C>A		intron_variant		ENST00000261200.9	NP_064693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9	c.4512+765C>A		intron_variant		5	NM_020297.4	ENSP00000261200.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.85
DEOGEN2	Benign	0.25	.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-0.55	.;N
PROVEAN	Benign	-0.94	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.12	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0010	.;B
Vest4		0.43
MutPred		0.37		.;Gain of sheet (P = 0.0827);
MVP		0.80
ClinPred		0.052	T
GERP RS		3.0
Varity_R		0.083

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

Publications

LitVar

Other links and lift over

dbSNP: rs142875103; hg19: chr12-21958167;