rs387906397

Variant names:

• chr11-47333192-A-C
• rs387906397
• NM_000256.3:c.3330+2T>G

Your query was ambiguous. Multiple possible variants found:

• chr11-47333192-A-C
• chr11-47333192-A-G
• chr11-47333192-A-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.3330+2T>G variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,601,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001434955: Analysis of cDNA extract from multiple carriers showed skipping of exon 30 as a result of this c.3330+2T>G change. PMID 17937428, 18258667, 18403758, 18467358, 25031304" and additional evidence is available in ClinVar. The gene MYBPC3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 8.93
• Publications: 20 publications found

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Specifications for MYBPC3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001434955: Analysis of cDNA extract from multiple carriers showed skipping of exon 30 as a result of this c.3330+2T>G change. PMID 17937428, 18258667, 18403758, 18467358, 25031304; SCV001451631: RNA isolated from patient cells showed that the splice donor variant resulted in skipping of exon 30, leading to premature truncation of the protein (PMID: 7493025; PMID: 17937428).; SCV004177064: Several functional studies show this variant causes skipping of exon 30 (also called exon 31 in some publications), leading to an out of frame transcript (Morita H et al., PMID: 18403758; Xin B et al., PMID: 17937428).; SCV000280260: Xin et al (2007) demonstrated that this variant led to skipping of exon 30 and creation of a frameshift and premature stop codon in exon 31. Theis et al (2008) studied myectomy samples from a carrier of this variant and also found an aberrant mRNA that led to a frameshift and premature stop codon. Immunohistochemistry revealed that the spatial organization of myosin binding protein C was severely disrupted.; SCV000284241: Studies have shown that disruption of this splice site results in skipping of exon 30, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 17937428, 25031304).; SCV004814320: Functional RNA studies have shown that this variant causes out-of-frame skipping of exon 30, resulting in premature protein truncation (PMID: 17937428, 18403758, 25031304).; SCV001359850: Functional RNA studies have shown that this variant causes out-of-frame skipping of exon 30, resulting in premature protein truncation (PMID: 17937428, 18403758, 25031304).; SCV002605812: RNA studies in patient lymphocytes indicate that this variant results in the skipping of exon 30, leading to a frame shift and premature protein truncation (Xin, 2007).; SCV004813530: At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a reduction in protein expression (Helms_2014).
• PP5: Variant 11-47333192-A-C is Pathogenic according to our data. Variant chr11-47333192-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 8621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.3330+2T>G		splice_donor intron	N/A	NP_000247.2	Q14896-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.3330+2T>G		splice_donor intron	N/A	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.3330+2T>G		splice_donor intron	N/A	ENSP00000382193.2	A8MXZ9

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449852 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 719834

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 43284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.00 AC: 0 AN: 39316

South Asian (SAS) AF: 0.00 AC: 0 AN: 83740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106346

Other (OTH) AF: 0.00 AC: 0 AN: 59918

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000806 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Hypertrophic cardiomyopathy 4 (6)
4	-	-	not provided (4)
3	-	-	Hypertrophic cardiomyopathy (3)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (1)
1	-	-	Left ventricular noncompaction 10 (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)
-	-	-	MYBPC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.9
GERP RS		5.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: 36
DS_DL_spliceai		1.0		Position offset: 2

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

Other links and lift over

dbSNP: rs387906397; hg19: chr11-47354743;