rs3729989

Variant names:

• chr11-47348490-T-C
• rs3729989
• NM_000256.3:c.706A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000256.3(MYBPC3):​c.706A>G​(p.Ser236Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,612,892 control chromosomes in the GnomAD database, including 12,149 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. The gene MYBPC3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.095 (786 hom., cov: 30)
  • Exomes 𝑓: 0.12 (11363 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 3.19
• Publications: 54 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 18 uncertain in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0027847886).
• BP6: Variant 11-47348490-T-C is Benign according to our data. Variant chr11-47348490-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

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.706A>G	p.Ser236Gly	missense	Exon 6 of 35	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.706A>G	p.Ser236Gly	missense	Exon 6 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.706A>G	p.Ser236Gly	missense	Exon 6 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.706A>G		non_coding_transcript_exon	Exon 6 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.0947 AC: 14397 AN: 152056 Hom.: 784 Cov.: 30

Gnomad AFR AF: 0.0535

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0746

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0276

Gnomad SAS AF: 0.0617

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.0889

GnomAD2 exomes AF: 0.0964 AC: 23868 AN: 247526 AF XY: 0.0978

Gnomad AFR exome AF: 0.0536

Gnomad AMR exome AF: 0.0459

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.0291

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.120 AC: 175560 AN: 1460718 Hom.: 11363 Cov.: 32 AF XY: 0.119 AC XY: 86305 AN XY: 726614

African (AFR) AF: 0.0521 AC: 1742 AN: 33464

American (AMR) AF: 0.0487 AC: 2176 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2809 AN: 26120

East Asian (EAS) AF: 0.0181 AC: 719 AN: 39682

South Asian (SAS) AF: 0.0704 AC: 6064 AN: 86138

European-Finnish (FIN) AF: 0.127 AC: 6756 AN: 53298

Middle Eastern (MID) AF: 0.109 AC: 628 AN: 5764

European-Non Finnish (NFE) AF: 0.133 AC: 147965 AN: 1111272

Other (OTH) AF: 0.111 AC: 6701 AN: 60334

GnomAD4 genome AF: 0.0947 AC: 14417 AN: 152174 Hom.: 786 Cov.: 30 AF XY: 0.0923 AC XY: 6869 AN XY: 74402

African (AFR) AF: 0.0539 AC: 2238 AN: 41528

American (AMR) AF: 0.0744 AC: 1138 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 373 AN: 3470

East Asian (EAS) AF: 0.0276 AC: 143 AN: 5172

South Asian (SAS) AF: 0.0622 AC: 300 AN: 4824

European-Finnish (FIN) AF: 0.121 AC: 1278 AN: 10588

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8690 AN: 67982

Other (OTH) AF: 0.0880 AC: 186 AN: 2114

Alfa AF: 0.115 Hom.: 5173

Bravo AF: 0.0894

TwinsUK AF: 0.135 AC: 501

ALSPAC AF: 0.135 AC: 519

ESP6500AA AF: 0.0574 AC: 239

ESP6500EA AF: 0.126 AC: 1060

ExAC AF: 0.100 AC: 12114

Asia WGS AF: 0.0500 AC: 174 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.129

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	Hypertrophic cardiomyopathy 4 (5)
-	-	4	Hypertrophic cardiomyopathy (4)
-	-	4	not provided (4)
-	-	2	Left ventricular noncompaction 10 (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.22
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.7	N
PhyloP100		3.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.031
MPC		0.20
ClinPred		0.0085	T
GERP RS		5.1
Varity_R		0.15
gMVP		0.44
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: rs3729989; hg19: chr11-47370041; COSMIC: COSV107223706;