rs398123280

Variant names:

• chr11-47335872-C-T
• rs398123280
• NM_000256.3:c.2737+5G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000256.3(MYBPC3):​c.2737+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000201 in 1,490,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYBPC3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 5.82
• Publications: 1 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-47335872-C-T is Pathogenic according to our data. Variant chr11-47335872-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92690.

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.2737+5G>A		splice_region 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.2737+5G>A		splice_region intron	N/A	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.2737+5G>A		splice_region intron	N/A	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.*242+5G>A		splice_region intron	N/A	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 30

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1338734 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 655788

African (AFR) AF: 0.00 AC: 0 AN: 28876

American (AMR) AF: 0.00 AC: 0 AN: 30060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23686

East Asian (EAS) AF: 0.00 AC: 0 AN: 31588

South Asian (SAS) AF: 0.00 AC: 0 AN: 72566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5242

European-Non Finnish (NFE) AF: 9.57e-7 AC: 1 AN: 1044488

Other (OTH) AF: 0.00 AC: 0 AN: 55156

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Hypertrophic cardiomyopathy (2)
1	1	-	not provided (2)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.96
PhyloP100		5.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: 5

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

Other links and lift over

dbSNP: rs398123280; hg19: chr11-47357423;