11-47333924-G-C

Variant names:

• chr11-47333924-G-C
• rs11570112
• NM_000256.3:c.2992C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000256.3(MYBPC3):​c.2992C>G​(p.Gln998Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,571,272 control chromosomes in the GnomAD database, including 55 homozygotes. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q998P) has been classified as Likely pathogenic. The gene MYBPC3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0026 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (48 hom.)
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Scores: Splicing: ADA: 0.6273
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 9.54
• Publications: 28 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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47333923-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1449122.
• BP4: Computational evidence support a benign effect (MetaRNN=0.011652589).
• BP6: Variant 11-47333924-G-C is Benign according to our data. Variant chr11-47333924-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00263 (401/152368) while in subpopulation AMR AF = 0.0197 (302/15302). AF 95% confidence interval is 0.0179. There are 7 homozygotes in GnomAd4. There are 220 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

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.2992C>G	p.Gln998Glu	missense splice_region	Exon 28 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.2992C>G	p.Gln998Glu	missense splice_region	Exon 28 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.2992C>G	p.Gln998Glu	missense splice_region	Exon 27 of 34	ENSP00000382193.2	A8MXZ9

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 403 AN: 152250 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0140

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00708 AC: 1305 AN: 184304 AF XY: 0.00564

Gnomad AFR exome AF: 0.000289

Gnomad AMR exome AF: 0.0387

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0160

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000770

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00149 AC: 2109 AN: 1418904 Hom.: 48 Cov.: 33 AF XY: 0.00135 AC XY: 947 AN XY: 701862

African (AFR) AF: 0.000247 AC: 8 AN: 32426

American (AMR) AF: 0.0381 AC: 1446 AN: 37972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25398

East Asian (EAS) AF: 0.0125 AC: 464 AN: 37226

South Asian (SAS) AF: 0.000496 AC: 40 AN: 80658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50488

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5672

European-Non Finnish (NFE) AF: 0.0000376 AC: 41 AN: 1090238

Other (OTH) AF: 0.00185 AC: 109 AN: 58826

GnomAD4 genome AF: 0.00263 AC: 401 AN: 152368 Hom.: 7 Cov.: 33 AF XY: 0.00295 AC XY: 220 AN XY: 74522

African (AFR) AF: 0.000264 AC: 11 AN: 41592

American (AMR) AF: 0.0197 AC: 302 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0139 AC: 72 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.000964 Hom.: 1

Bravo AF: 0.00511

ExAC AF: 0.00347 AC: 416

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	6	not specified (6)
-	-	4	Hypertrophic cardiomyopathy 4 (4)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (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;C0878544:Cardiomyopathy (1)
-	-	1	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.9	L
PhyloP100		9.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Vest4		0.90
MVP		0.89
MPC		0.85
ClinPred		0.056	T
GERP RS		4.1
Varity_R		0.46
gMVP		0.68
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.63
dbscSNV1_RF	Benign	0.44
Splicevardb		2.0
SpliceAI score (max)		0.11		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: rs11570112; hg19: chr11-47355475; COSMIC: COSV57026168; COSMIC: COSV57026168;