Genetic Variant ABCC9:c.1165-8_1165-6delTTT (chr12-21910317-CAAA-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_020297.4(ABCC9):c.1165-8_1165-6delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,383,166 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000017 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00045 ( 0 hom. )

Consequence

ABCC9
NM_020297.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.57

Publications

6 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
dilated cardiomyopathy 1O
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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 Submitted by: 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC9	NM_020297.4 link	c.1165-8_1165-6delTTT		splice_region_variant, intron_variant	Intron 9 of 39	ENST00000261200.9	NP_064693.2	O60706-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9 link	c.1165-8_1165-6delTTT		splice_region_variant, intron_variant	Intron 9 of 39	5	NM_020297.4	ENSP00000261200.4		O60706-2

Frequencies

GnomAD3 genomes

AF:

0.0000169

AC:

AN:

118564

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000179

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00119

AC:

169

AN:

142000

AF XY:

0.00128

show subpopulations

Gnomad AFR exome

AF:

0.000429

Gnomad AMR exome

AF:

0.00123

Gnomad ASJ exome

AF:

0.00158

Gnomad EAS exome

AF:

0.000937

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.000447

AC:

565

AN:

1264602

Hom.:

AF XY:

0.000453

AC XY:

286

AN XY:

631286

show subpopulations

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

African (AFR)

AF:

0.000329

AC:

AN:

27382

American (AMR)

AF:

0.00156

AC:

AN:

32732

Ashkenazi Jewish (ASJ)

AF:

0.000485

AC:

AN:

22682

East Asian (EAS)

AF:

0.000253

AC:

AN:

35530

South Asian (SAS)

AF:

0.000750

AC:

AN:

71958

European-Finnish (FIN)

AF:

0.000780

AC:

AN:

38480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4908

European-Non Finnish (NFE)

AF:

0.000388

AC:

380

AN:

978172

Other (OTH)

AF:

0.000398

AC:

AN:

52758

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.247

Heterozygous variant carriers

169

253

338

422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000169

AC:

AN:

118564

Hom.:

Cov.:

AF XY:

0.0000176

AC XY:

AN XY:

56900

show subpopulations

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

African (AFR)

AF:

0.0000322

AC:

AN:

31058

American (AMR)

AF:

0.00

AC:

AN:

11938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2766

East Asian (EAS)

AF:

0.00

AC:

AN:

3892

South Asian (SAS)

AF:

0.00

AC:

AN:

3828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000179

AC:

AN:

55902

Other (OTH)

AF:

0.00

AC:

AN:

1624

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=89/11

polymorphism

(source)

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

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12-21910317-CAAAAA-CAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over