11-47335928-C-T

Variant names:

• chr11-47335928-C-T
• rs35078470
• NM_000256.3:c.2686G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000256.3(MYBPC3):​c.2686G>A​(p.Val896Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00554 in 1,553,518 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. V896G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (8 hom., cov: 30)
  • Exomes 𝑓: 0.0055 (50 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 1.01
• Publications: 30 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008191198).
• BP6: Variant 11-47335928-C-T is Benign according to our data. Variant chr11-47335928-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00571 (869/152294) while in subpopulation NFE AF = 0.0074 (503/68016). AF 95% confidence interval is 0.00686. There are 8 homozygotes in GnomAd4. There are 468 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD 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.2686G>A	p.Val896Met	missense	Exon 26 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.2686G>A	p.Val896Met	missense	Exon 26 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.2686G>A	p.Val896Met	missense	Exon 25 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.*191G>A		non_coding_transcript_exon	Exon 26 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.00571 AC: 869 AN: 152176 Hom.: 8 Cov.: 30

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00739

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00574 AC: 996 AN: 173634 AF XY: 0.00568

Gnomad AFR exome AF: 0.00157

Gnomad AMR exome AF: 0.000443

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.00600

Gnomad OTH exome AF: 0.00412

GnomAD4 exome AF: 0.00553 AC: 7742 AN: 1401224 Hom.: 50 Cov.: 34 AF XY: 0.00552 AC XY: 3822 AN XY: 692280

African (AFR) AF: 0.000446 AC: 14 AN: 31368

American (AMR) AF: 0.000552 AC: 20 AN: 36200

Ashkenazi Jewish (ASJ) AF: 0.000162 AC: 4 AN: 24710

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35888

South Asian (SAS) AF: 0.000749 AC: 59 AN: 78772

European-Finnish (FIN) AF: 0.0261 AC: 1309 AN: 50202

Middle Eastern (MID) AF: 0.000851 AC: 4 AN: 4702

European-Non Finnish (NFE) AF: 0.00559 AC: 6043 AN: 1081520

Other (OTH) AF: 0.00498 AC: 288 AN: 57862

GnomAD4 genome AF: 0.00571 AC: 869 AN: 152294 Hom.: 8 Cov.: 30 AF XY: 0.00629 AC XY: 468 AN XY: 74460

African (AFR) AF: 0.000481 AC: 20 AN: 41568

American (AMR) AF: 0.00320 AC: 49 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0271 AC: 287 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00740 AC: 503 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00532 Hom.: 8

Bravo AF: 0.00346

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00151 AC: 6

ESP6500EA AF: 0.00482 AC: 40

ExAC AF: 0.00452 AC: 543

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Hypertrophic cardiomyopathy (4)
-	-	4	Hypertrophic cardiomyopathy 4 (4)
-	-	4	not provided (4)
-	-	3	Primary familial hypertrophic cardiomyopathy (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (1)
-	-	1	Left ventricular noncompaction 10 (1)
-	-	1	MYBPC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.21
Sift	Uncertain	0.026	D
Sift4G	Benign	0.069	T
Vest4		0.18
MVP		0.65
MPC		0.23
ClinPred		0.011	T
GERP RS		2.2
Varity_R		0.20
gMVP		0.36
Mutation Taster		=99/1	polymorphism

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: rs35078470; hg19: chr11-47357479;