rs771875597

Variant names:

• chr11-47346629-C-G
• rs771875597
• NM_000256.3:c.924G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-47346629-C-G
• chr11-47346629-C-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_000256.3(MYBPC3):​c.924G>C​(p.Pro308Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P308P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001529
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.54
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-47346629-C-G is Benign according to our data. Variant chr11-47346629-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1879202.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.54 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.924G>C	p.Pro308Pro	splice_region_variant, synonymous_variant	Exon 11 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.924G>C	p.Pro308Pro	splice_region_variant, synonymous_variant	Exon 11 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.924G>C	p.Pro308Pro	splice_region_variant, synonymous_variant	Exon 10 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.924G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 11 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000853 AC: 11 AN: 128992 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00105

Gnomad SAS AF: 0.000287

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000483

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00175 AC: 1220 AN: 697806 Hom.: 0 Cov.: 31 AF XY: 0.00153 AC XY: 546 AN XY: 356828

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

African (AFR) AF: 0.00162 AC: 26 AN: 16090

American (AMR) AF: 0.000189 AC: 6 AN: 31718

Ashkenazi Jewish (ASJ) AF: 0.00102 AC: 13 AN: 12754

East Asian (EAS) AF: 0.000759 AC: 12 AN: 15802

South Asian (SAS) AF: 0.000339 AC: 23 AN: 67826

European-Finnish (FIN) AF: 0.000299 AC: 10 AN: 33486

Middle Eastern (MID) AF: 0.00208 AC: 7 AN: 3372

European-Non Finnish (NFE) AF: 0.00220 AC: 1078 AN: 489254

Other (OTH) AF: 0.00164 AC: 45 AN: 27504

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000930 AC: 12 AN: 129076 Hom.: 0 Cov.: 30 AF XY: 0.0000812 AC XY: 5 AN XY: 61604

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

African (AFR) AF: 0.0000291 AC: 1 AN: 34390

American (AMR) AF: 0.000169 AC: 2 AN: 11818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3244

East Asian (EAS) AF: 0.00105 AC: 4 AN: 3796

South Asian (SAS) AF: 0.000288 AC: 1 AN: 3470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 250

European-Non Finnish (NFE) AF: 0.0000644 AC: 4 AN: 62108

Other (OTH) AF: 0.00 AC: 0 AN: 1786

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYBPC3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.085
DANN	Benign	0.21
PhyloP100		-3.5
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.096
SpliceAI score (max)		0.040		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: rs771875597; hg19: chr11-47368180;