rs2856653

Variant names:

• chr11-47339533-T-C
• rs2856653
• NM_000256.3:c.2067+118A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000256.3(MYBPC3):​c.2067+118A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 1,483,902 control chromosomes in the GnomAD database, including 336,355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35900 hom., cov: 32)
  • Exomes 𝑓: 0.67 (300455 hom.)
• Consequence: MYBPC3 NM_000256.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.68
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-47339533-T-C is Benign according to our data. Variant chr11-47339533-T-C is described in ClinVar as Benign. ClinVar VariationId is 1241464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2067+118A>G		intron_variant	Intron 21 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2067+118A>G		intron_variant	Intron 21 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2067+118A>G		intron_variant	Intron 20 of 33	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2067+118A>G		intron_variant	Intron 21 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.684 AC: 103921 AN: 152002 Hom.: 35879 Cov.: 32

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.743

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.767

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.669

GnomAD4 exome AF: 0.668 AC: 889448 AN: 1331784 Hom.: 300455 Cov.: 22 AF XY: 0.669 AC XY: 439372 AN XY: 656362

African (AFR) AF: 0.681 AC: 21040 AN: 30900

American (AMR) AF: 0.815 AC: 29662 AN: 36410

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 13845 AN: 21640

East Asian (EAS) AF: 0.982 AC: 37438 AN: 38124

South Asian (SAS) AF: 0.759 AC: 56146 AN: 74006

European-Finnish (FIN) AF: 0.699 AC: 34460 AN: 49298

Middle Eastern (MID) AF: 0.647 AC: 3415 AN: 5278

European-Non Finnish (NFE) AF: 0.642 AC: 655621 AN: 1020640

Other (OTH) AF: 0.682 AC: 37821 AN: 55488

GnomAD4 genome AF: 0.684 AC: 103989 AN: 152118 Hom.: 35900 Cov.: 32 AF XY: 0.691 AC XY: 51406 AN XY: 74354

African (AFR) AF: 0.687 AC: 28469 AN: 41462

American (AMR) AF: 0.744 AC: 11370 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2214 AN: 3472

East Asian (EAS) AF: 0.979 AC: 5074 AN: 5184

South Asian (SAS) AF: 0.767 AC: 3701 AN: 4826

European-Finnish (FIN) AF: 0.702 AC: 7432 AN: 10590

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.640 AC: 43535 AN: 67972

Other (OTH) AF: 0.672 AC: 1421 AN: 2114

Alfa AF: 0.649 Hom.: 13543

Bravo AF: 0.688

Asia WGS AF: 0.850 AC: 2954 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: 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	-0.89
CADD	Benign	0.027
DANN	Benign	0.35
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2856653; hg19: chr11-47361084;