rs34580776

Variant names:

• chr11-47346320-C-T
• rs34580776
• NM_000256.3:c.977G>A
• MYBPC3 p.Arg326Gln

Your query was ambiguous. Multiple possible variants found:

• chr11-47346320-C-T
• chr11-47346320-C-A

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -10 classification points (ACMG Germline Pathogenicity v2019). BS2BP4_ModerateBP6_Strong

The NM_000256.3(MYBPC3):c.977G>A (p.Arg326Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.003 (AC=4,842) in the gnomAD database across 1,611,640 control chromosomes, including 28 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00453. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R326= (synonymous): Likely_benign (ClinVar VariationId 1535531, 1 star); p.R326W: Uncertain_significance (ClinVar VariationId 525027, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (27 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29
• Conservation: PhyloP100: 1.16
• Publications: 36 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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, G2P
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD, AR Classification: LIMITED Submitted by: ClinGen
• familial dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: G2P

Classification according to ACMG Germline Pathogenicity v2019

Specifications for MYBPC3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Benign. The variant received -10 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (29/29 total B/LB).
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 28.; Very high cumulative gnomAD AC = 4842 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.977G>A	p.Arg326Gln	missense	Exon 12 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.977G>A	p.Arg326Gln	missense	Exon 12 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.977G>A	p.Arg326Gln	missense	Exon 11 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.977G>A		non_coding_transcript_exon	Exon 12 of 27	ENSP00000444259.1	F5GZR4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00348	AC:530	Hom:1	AN:152196	Cov:32
GnomAD2 exomes	AF: 0.00406	AC:991	Hom:	AN:243898	Cov:
GnomAD4 exome	AF: 0.00295	AC:4312	Hom:27	AN:1459328	Cov:32
GnomAD4 genome	AF: 0.00348	AC:530	Hom:1	AN:152312	Cov:32
TOPMed (Bravo)	AF: 0.00197	AC:521	Hom:3	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00378	AC:381	Hom:5	AN:100708	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00171	AC:4	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.00333	AC:1	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00249	AC:32	Hom:	AN:12852	Cov:
Qatari Genome	AF: 0.0114	AC:2	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000160	AC:2	Hom:0	AN:122496	Cov:
Turkish Variome	AF: 0.00567	AC:38	Hom:0	AN:6702	Cov:
UK10K	AF: 0.000926	AC:7	Hom:	AN:7562	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00923 *	13	1408	0.00750 *	53	7062
BipEx(Bipolar disorder (including schizoaffective))	0.00415	118	28416	0.00420	121	28838
Epi25(Epilepsy)	0.00472	198	41958	0.00292	195	66854
SCHEMA(Schizophrenia)	0.00300	339	113008	0.00330	627	190258

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

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 (5)
-	-	5	Hypertrophic cardiomyopathy 4 (5)
-	-	4	not provided (4)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1A (1)
-	-	1	Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (1)
-	-	1	Left ventricular noncompaction 10 (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Primary dilated cardiomyopathy;C0151636:Premature ventricular contraction (1)
-	-	1	Primary familial hypertrophic cardiomyopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.054
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.89	D
GPN-Star LLR	N/A	-5.7
GPN-Star score	N/A	5.7
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.78	T
Mutation Taster	N/A	98/2	polymorphism
MutationAssessor	Uncertain	2.2	M
PhyloP100	Benign	1.2
popEVE	Benign	-3.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.078
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.048	D
Varity_R	N/A	0.16
VESM-3B	Benign	-7.7

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.070	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34580776;

hg19: chr11-47367871;

COSMIC: COSV57033344;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar