11-47336021-G-C

Variant names:

• chr11-47336021-G-C
• rs765120057
• NM_000256.3:c.2603-10C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000256.3(MYBPC3):​c.2603-10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,346,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 intron
• Scores: Splicing: ADA: 0.0002118
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.622
• Publications: 0 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD 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
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2603-10C>G		intron_variant	Intron 25 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2603-10C>G		intron_variant	Intron 25 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2603-10C>G		intron_variant	Intron 24 of 33	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.*108-10C>G		intron_variant	Intron 25 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1346450 Hom.: 0 Cov.: 33 AF XY: 0.00000152 AC XY: 1 AN XY: 659308

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

African (AFR) AF: 0.00 AC: 0 AN: 29482

American (AMR) AF: 0.00 AC: 0 AN: 31656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20520

East Asian (EAS) AF: 0.00 AC: 0 AN: 35566

South Asian (SAS) AF: 0.00 AC: 0 AN: 67302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3706

European-Non Finnish (NFE) AF: 9.49e-7 AC: 1 AN: 1053488

Other (OTH) AF: 0.00 AC: 0 AN: 55298

⚠️ 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 Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.61
PhyloP100		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.016
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: rs765120057; hg19: chr11-47357572;