rs193922380

Variant names:

• chr11-47335077-G-C
• rs193922380
• NM_000256.3:c.2870C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-47335077-G-C
• chr11-47335077-G-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000256.3(MYBPC3):​c.2870C>G​(p.Thr957Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,595,244 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYBPC3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00087 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:12
• Conservation: PhyloP100: 1.07
• Publications: 15 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02241832).
• BP6: Variant 11-47335077-G-C is Benign according to our data. Variant chr11-47335077-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36607.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.2870C>G	p.Thr957Ser	missense	Exon 27 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.2870C>G	p.Thr957Ser	missense	Exon 27 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.2870C>G	p.Thr957Ser	missense	Exon 26 of 34	ENSP00000382193.2	A8MXZ9

Frequencies

GnomAD3 genomes AF: 0.000867 AC: 132 AN: 152236 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00101 AC: 237 AN: 235526 AF XY: 0.00110

Gnomad AFR exome AF: 0.000205

Gnomad AMR exome AF: 0.000649

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.000354

GnomAD4 exome AF: 0.00170 AC: 2459 AN: 1442890 Hom.: 4 Cov.: 31 AF XY: 0.00161 AC XY: 1150 AN XY: 716100

African (AFR) AF: 0.000336 AC: 11 AN: 32756

American (AMR) AF: 0.000627 AC: 27 AN: 43076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25484

East Asian (EAS) AF: 0.00 AC: 0 AN: 38756

South Asian (SAS) AF: 0.000836 AC: 70 AN: 83770

European-Finnish (FIN) AF: 0.000416 AC: 22 AN: 52858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00202 AC: 2228 AN: 1100974

Other (OTH) AF: 0.00170 AC: 101 AN: 59510

GnomAD4 genome AF: 0.000866 AC: 132 AN: 152354 Hom.: 1 Cov.: 33 AF XY: 0.000832 AC XY: 62 AN XY: 74502

African (AFR) AF: 0.000313 AC: 13 AN: 41586

American (AMR) AF: 0.000522 AC: 8 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 68026

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00148 Hom.: 1

Bravo AF: 0.000865

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00133 AC: 11

ExAC AF: 0.000993 AC: 120

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	3	not specified (4)
-	-	2	Cardiomyopathy (2)
-	2	-	Hypertrophic cardiomyopathy 4 (2)
-	1	1	Primary familial hypertrophic cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	1	-	Left ventricular noncompaction 10 (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
CardioboostCm	Benign	0.00078
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.29
Sift	Benign	0.35	T
Sift4G	Benign	0.20	T
Vest4		0.67
MVP		0.75
MPC		0.20
ClinPred		0.024	T
GERP RS		0.79
Varity_R		0.13
gMVP		0.28
Mutation Taster		=21/79	disease causing

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: rs193922380; hg19: chr11-47356628; COSMIC: COSV57027162; COSMIC: COSV57027162;