12-21915915-G-T

Position:

• chr12-21915915-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020297.4(ABCC9):​c.574-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 1,605,848 control chromosomes in the GnomAD database, including 286,598 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27476 hom., cov: 29)
  • Exomes 𝑓: 0.59 (259122 hom.)
• Consequence: ABCC9 NM_020297.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002551
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.499

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-21915915-G-T is Benign according to our data. Variant chr12-21915915-G-T is described in ClinVar as [Benign]. Clinvar id is 45419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21915915-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC9	NM_020297.4	c.574-5C>A		splice_region_variant, intron_variant		ENST00000261200.9	NP_064693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC9	ENST00000261200.9	c.574-5C>A		splice_region_variant, intron_variant		5	NM_020297.4	ENSP00000261200.4

Frequencies

GnomAD3 genomes AF: 0.600 AC: 90862 AN: 151440 Hom.: 27456 Cov.: 29

Gnomad AFR AF: 0.585

Gnomad AMI AF: 0.517

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.714

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.613

GnomAD3 exomes AF: 0.610 AC: 151317 AN: 247920 Hom.: 46884 AF XY: 0.615 AC XY: 82676 AN XY: 134388

Gnomad AFR exome AF: 0.581

Gnomad AMR exome AF: 0.544

Gnomad ASJ exome AF: 0.705

Gnomad EAS exome AF: 0.790

Gnomad SAS exome AF: 0.643

Gnomad FIN exome AF: 0.592

Gnomad NFE exome AF: 0.591

Gnomad OTH exome AF: 0.623

GnomAD4 exome AF: 0.594 AC: 864135 AN: 1454286 Hom.: 259122 Cov.: 33 AF XY: 0.597 AC XY: 432206 AN XY: 723728

Gnomad4 AFR exome AF: 0.576

Gnomad4 AMR exome AF: 0.546

Gnomad4 ASJ exome AF: 0.711

Gnomad4 EAS exome AF: 0.775

Gnomad4 SAS exome AF: 0.642

Gnomad4 FIN exome AF: 0.591

Gnomad4 NFE exome AF: 0.582

Gnomad4 OTH exome AF: 0.616

GnomAD4 genome AF: 0.600 AC: 90934 AN: 151562 Hom.: 27476 Cov.: 29 AF XY: 0.602 AC XY: 44542 AN XY: 74006

Gnomad4 AFR AF: 0.585

Gnomad4 AMR AF: 0.571

Gnomad4 ASJ AF: 0.704

Gnomad4 EAS AF: 0.795

Gnomad4 SAS AF: 0.634

Gnomad4 FIN AF: 0.598

Gnomad4 NFE AF: 0.594

Gnomad4 OTH AF: 0.617

Alfa AF: 0.604 Hom.: 44823

Bravo AF: 0.596

Asia WGS AF: 0.673 AC: 2335 AN: 3478

EpiCase AF: 0.609

EpiControl AF: 0.607

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 19, 2011	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrichotic osteochondrodysplasia Cantu type Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Dilated cardiomyopathy 1O Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.4
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -32

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

Publications

LitVar

Other links and lift over

dbSNP: rs3759236; hg19: chr12-22068849;