dbSNP rs61688134: ABCC9:p.Val734Ile (chr12-21864476-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020297.4(ABCC9):c.2200G>A(p.Val734Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,587,612 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0074 ( 4 hom., cov: 32)

Exomes 𝑓: 0.011 ( 93 hom. )

Consequence

ABCC9
NM_020297.4 missense, splice_region

Scores

Splicing: ADA: 0.03439

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:16

Conservation

PhyloP100: 2.92

Publications

29 publications found

Variant links:

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)

ABCC9 links:

ENSG00000257022 (HGNC:):

ENSG00000257022 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008691698).

BP6

Variant 12-21864476-C-T is Benign according to our data. Variant chr12-21864476-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35627.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00736 (1120/152264) while in subpopulation NFE AF = 0.0118 (803/68010). AF 95% confidence interval is 0.0111. There are 4 homozygotes in GnomAd4. There are 506 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCC9	NM_020297.4	MANE Select	c.2200G>A	p.Val734Ile	missense splice_region	Exon 19 of 40	NP_064693.2	O60706-2
ABCC9	NM_001377273.1		c.2200G>A	p.Val734Ile	missense splice_region	Exon 20 of 41	NP_001364202.1	O60706-2
ABCC9	NM_005691.4		c.2200G>A	p.Val734Ile	missense splice_region	Exon 19 of 41	NP_005682.2	O60706-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCC9	ENST00000261200.9	TSL:5 MANE Select	c.2200G>A	p.Val734Ile	missense splice_region	Exon 19 of 40	ENSP00000261200.4	O60706-2
ABCC9	ENST00000261201.10	TSL:5	c.2200G>A	p.Val734Ile	missense splice_region	Exon 19 of 41	ENSP00000261201.4	O60706-1
ABCC9	ENST00000879186.1		c.2200G>A	p.Val734Ile	missense splice_region	Exon 18 of 39	ENSP00000549245.1

Frequencies

GnomAD3 genomes

AF:

0.00736

AC:

1120

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00911

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00736

AC:

1844

AN:

250682

AF XY:

0.00730

show subpopulations

Gnomad AFR exome

AF:

0.00235

Gnomad AMR exome

AF:

0.00993

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00333

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.00787

GnomAD4 exome

AF:

0.0107

AC:

15378

AN:

1435348

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

7422

AN XY:

715544

show subpopulations

African (AFR)

AF:

0.00225

AC:

AN:

32898

American (AMR)

AF:

0.0102

AC:

456

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.00355

AC:

AN:

25950

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39494

South Asian (SAS)

AF:

0.0000350

AC:

AN:

85760

European-Finnish (FIN)

AF:

0.00320

AC:

171

AN:

53380

Middle Eastern (MID)

AF:

0.00280

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.0128

AC:

13979

AN:

1088070

Other (OTH)

AF:

0.00985

AC:

586

AN:

59476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

623

1246

1868

2491

3114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

542

1084

1626

2168

2710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00736

AC:

1120

AN:

152264

Hom.:

Cov.:

AF XY:

0.00680

AC XY:

506

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00253

AC:

105

AN:

41558

American (AMR)

AF:

0.00909

AC:

139

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00377

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0118

AC:

803

AN:

68010

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00983

Hom.:

Bravo

AF:

0.00812

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0132

AC:

113

ExAC

AF:

0.00698

AC:

847

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0118

EpiControl

AF:

0.0119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (3)

Dilated cardiomyopathy 1O (2)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Myocardial infarction (1)

Ventricular tachycardia;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.15

Eigen_PC

Benign

0.053

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.78

PhyloP100

2.9

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.10

REVEL

Benign

0.29

Sift

Benign

0.31

Sift4G

Benign

0.52

Polyphen

0.0040

Vest4

0.25

MVP

0.83

MPC

0.54

ClinPred

0.014

GERP RS

5.0

Varity_R

0.093

gMVP

0.25

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.034

dbscSNV1_RF

Benign

0.19

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.29

Position offset: 1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over