rs3218719

Variant names:

• chr11-47350027-G-A
• rs3218719
• NM_000256.3:c.492C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_000256.3(MYBPC3):​c.492C>T​(p.Gly164Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,561,180 control chromosomes in the GnomAD database, including 778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (50 hom., cov: 33)
  • Exomes 𝑓: 0.030 (728 hom.)
• Consequence: MYBPC3 NM_000256.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.116
• Publications: 12 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 11-47350027-G-A is Benign according to our data. Variant chr11-47350027-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42760.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 = 0.0211 (3214/152020) while in subpopulation NFE AF = 0.0329 (2233/67952). AF 95% confidence interval is 0.0317. There are 50 homozygotes in GnomAd4. There are 1456 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 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.492C>T	p.Gly164Gly	synonymous	Exon 4 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.492C>T	p.Gly164Gly	synonymous	Exon 4 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.492C>T	p.Gly164Gly	synonymous	Exon 4 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.492C>T		non_coding_transcript_exon	Exon 4 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3213 AN: 151902 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00634

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0335

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0329

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0207 AC: 3518 AN: 170188 AF XY: 0.0206

Gnomad AFR exome AF: 0.00506

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0344

Gnomad EAS exome AF: 0.000166

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.0317

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0301 AC: 42432 AN: 1409160 Hom.: 728 Cov.: 37 AF XY: 0.0294 AC XY: 20447 AN XY: 696138

African (AFR) AF: 0.00453 AC: 145 AN: 32004

American (AMR) AF: 0.0136 AC: 504 AN: 37044

Ashkenazi Jewish (ASJ) AF: 0.0344 AC: 869 AN: 25294

East Asian (EAS) AF: 0.0000823 AC: 3 AN: 36460

South Asian (SAS) AF: 0.00452 AC: 361 AN: 79846

European-Finnish (FIN) AF: 0.0247 AC: 1230 AN: 49740

Middle Eastern (MID) AF: 0.0250 AC: 142 AN: 5672

European-Non Finnish (NFE) AF: 0.0346 AC: 37539 AN: 1084734

Other (OTH) AF: 0.0281 AC: 1639 AN: 58366

GnomAD4 genome AF: 0.0211 AC: 3214 AN: 152020 Hom.: 50 Cov.: 33 AF XY: 0.0196 AC XY: 1456 AN XY: 74348

African (AFR) AF: 0.00634 AC: 263 AN: 41478

American (AMR) AF: 0.0154 AC: 236 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0335 AC: 116 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4826

European-Finnish (FIN) AF: 0.0258 AC: 272 AN: 10528

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0329 AC: 2233 AN: 67952

Other (OTH) AF: 0.0199 AC: 42 AN: 2112

Alfa AF: 0.0297 Hom.: 121

Bravo AF: 0.0196

Asia WGS AF: 0.00635 AC: 22 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)
-	-	3	not provided (3)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Left ventricular noncompaction 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.75
PhyloP100		0.12
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.55		Position offset: 2

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

Other links and lift over

dbSNP: rs3218719; hg19: chr11-47371578; COSMIC: COSV57023298; COSMIC: COSV57023298;