rs1411076886

Variant names:

• chr12-21910317-C-A
• rs1411076886
• NM_020297.4:c.1165-5G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-21910317-C-A
• chr12-21910317-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_020297.4(ABCC9):​c.1165-5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000659 in 1,270,118 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00066 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC9 NM_020297.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001579
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -0.270
• Publications: 1 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: 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)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-21910317-C-A is Benign according to our data. Variant chr12-21910317-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 464654.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC9	NM_020297.4	c.1165-5G>T		splice_region_variant, intron_variant	Intron 9 of 39	ENST00000261200.9	NP_064693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9	c.1165-5G>T		splice_region_variant, intron_variant	Intron 9 of 39	5	NM_020297.4	ENSP00000261200.4

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 414 AN: 117952 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00386

Gnomad AMI AF: 0.00135

Gnomad AMR AF: 0.00252

Gnomad ASJ AF: 0.00182

Gnomad EAS AF: 0.00363

Gnomad SAS AF: 0.00367

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00476

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.00433

GnomAD2 exomes AF: 0.00161 AC: 228 AN: 142000 AF XY: 0.00166

Gnomad AFR exome AF: 0.00236

Gnomad AMR exome AF: 0.00184

Gnomad ASJ exome AF: 0.00193

Gnomad EAS exome AF: 0.00354

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000584

GnomAD4 exome AF: 0.000659 AC: 837 AN: 1270118 Hom.: 1 Cov.: 27 AF XY: 0.000727 AC XY: 461 AN XY: 634026

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

African (AFR) AF: 0.00193 AC: 53 AN: 27464

American (AMR) AF: 0.00359 AC: 118 AN: 32890

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 33 AN: 22786

East Asian (EAS) AF: 0.00230 AC: 82 AN: 35606

South Asian (SAS) AF: 0.00174 AC: 126 AN: 72236

European-Finnish (FIN) AF: 0.00181 AC: 70 AN: 38688

Middle Eastern (MID) AF: 0.00102 AC: 5 AN: 4908

European-Non Finnish (NFE) AF: 0.000304 AC: 299 AN: 982514

Other (OTH) AF: 0.000962 AC: 51 AN: 53026

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00352 AC: 415 AN: 117962 Hom.: 0 Cov.: 23 AF XY: 0.00381 AC XY: 216 AN XY: 56680

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

African (AFR) AF: 0.00392 AC: 121 AN: 30904

American (AMR) AF: 0.00252 AC: 30 AN: 11912

Ashkenazi Jewish (ASJ) AF: 0.00182 AC: 5 AN: 2748

East Asian (EAS) AF: 0.00363 AC: 14 AN: 3854

South Asian (SAS) AF: 0.00343 AC: 13 AN: 3792

European-Finnish (FIN) AF: 0.0120 AC: 79 AN: 6578

Middle Eastern (MID) AF: 0.00526 AC: 1 AN: 190

European-Non Finnish (NFE) AF: 0.00259 AC: 144 AN: 55620

Other (OTH) AF: 0.00431 AC: 7 AN: 1624

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00278 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1O Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.2
DANN	Benign	0.54
PhyloP100		-0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs1411076886; hg19: chr12-22063251;