rs3729948

Variant names:

• chr11-47338502-G-C
• rs3729948
• NM_000256.3:c.2308+18C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000256.3(MYBPC3):​c.2308+18C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0428 in 1,613,746 control chromosomes in the GnomAD database, including 1,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (265 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1695 hom.)
• Consequence: MYBPC3 NM_000256.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.644
• Publications: 8 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: 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: AD, AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-47338502-G-C is Benign according to our data. Variant chr11-47338502-G-C is described in ClinVar as Benign. ClinVar VariationId is 188566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.11 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.2308+18C>G		intron	N/A	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.2308+18C>G		intron	N/A	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.2308+18C>G		intron	N/A	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.2308+18C>G		intron	N/A	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 7736 AN: 152156 Hom.: 266 Cov.: 32

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.0433

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0382

Gnomad OTH AF: 0.0445

GnomAD2 exomes AF: 0.0483 AC: 12007 AN: 248776 AF XY: 0.0515

Gnomad AFR exome AF: 0.0826

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.0381

Gnomad FIN exome AF: 0.0499

Gnomad NFE exome AF: 0.0392

Gnomad OTH exome AF: 0.0361

GnomAD4 exome AF: 0.0419 AC: 61298 AN: 1461472 Hom.: 1695 Cov.: 31 AF XY: 0.0441 AC XY: 32047 AN XY: 727024

African (AFR) AF: 0.0843 AC: 2821 AN: 33478

American (AMR) AF: 0.0170 AC: 762 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 330 AN: 26134

East Asian (EAS) AF: 0.0353 AC: 1402 AN: 39696

South Asian (SAS) AF: 0.112 AC: 9693 AN: 86238

European-Finnish (FIN) AF: 0.0501 AC: 2670 AN: 53308

Middle Eastern (MID) AF: 0.0319 AC: 184 AN: 5764

European-Non Finnish (NFE) AF: 0.0366 AC: 40691 AN: 1111778

Other (OTH) AF: 0.0455 AC: 2745 AN: 60366

GnomAD4 genome AF: 0.0508 AC: 7739 AN: 152274 Hom.: 265 Cov.: 32 AF XY: 0.0513 AC XY: 3816 AN XY: 74450

African (AFR) AF: 0.0804 AC: 3341 AN: 41542

American (AMR) AF: 0.0227 AC: 348 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3470

East Asian (EAS) AF: 0.0426 AC: 221 AN: 5182

South Asian (SAS) AF: 0.118 AC: 567 AN: 4822

European-Finnish (FIN) AF: 0.0465 AC: 494 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0381 AC: 2595 AN: 68022

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0435 Hom.: 34

Bravo AF: 0.0481

Asia WGS AF: 0.119 AC: 413 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hypertrophic cardiomyopathy 4 (3)
-	-	3	not specified (3)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.0
DANN	Benign	0.57
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs3729948; hg19: chr11-47360053; COSMIC: COSV57027816;