rs397517186

Positions:

• chr12-21882785-G-A
• chr12-21882785-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_020297.4(ABCC9):​c.2000C>T​(p.Thr667Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,460,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ABCC9 NM_020297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• 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 7.023 (greater than threshold 3.09). GenCC has associacion of 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=0.17283973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC9	NM_020297.4	c.2000C>T	p.Thr667Ile	missense_variant	16/40	ENST00000261200.9	NP_064693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9	c.2000C>T	p.Thr667Ile	missense_variant	16/40	5	NM_020297.4	ENSP00000261200.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251320 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460548 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726674

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1O Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2022

This variant is present in population databases (rs397517186, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 667 of the ABCC9 protein (p.Thr667Ile). This variant has not been reported in the literature in individuals affected with ABCC9-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1462649). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.76
DEOGEN2	Benign	0.33	.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.19
Sift	Benign	0.23	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.0	B;B
Vest4		0.23
MutPred		0.32		Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);
MVP		0.74
MPC		0.72
ClinPred		0.12	T
GERP RS		4.5
Varity_R		0.070
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs397517186; hg19: chr12-22035719;