rs397515993

Variant names:

• chr11-47351241-G-A
• rs397515993
• NM_000256.3:c.290C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-47351241-G-A
• chr11-47351241-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000256.3(MYBPC3):​c.290C>T​(p.Ala97Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000725 in 1,379,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A97S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Scores: Splicing: ADA: 0.1754
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 6.11
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47351241-G-A is Pathogenic according to our data. Variant chr11-47351241-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42670.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18076849). . Strength limited to SUPPORTING due to the PP5.

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.290C>T	p.Ala97Val	missense splice_region	Exon 2 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.290C>T	p.Ala97Val	missense splice_region	Exon 2 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.290C>T	p.Ala97Val	missense splice_region	Exon 2 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.290C>T		splice_region non_coding_transcript_exon	Exon 2 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1379800 Hom.: 0 Cov.: 37 AF XY: 0.00000148 AC XY: 1 AN XY: 675624

African (AFR) AF: 0.00 AC: 0 AN: 31566

American (AMR) AF: 0.00 AC: 0 AN: 36046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24260

East Asian (EAS) AF: 0.00 AC: 0 AN: 35622

South Asian (SAS) AF: 0.00 AC: 0 AN: 77912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5392

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062686

Other (OTH) AF: 0.0000175 AC: 1 AN: 57036

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hypertrophic cardiomyopathy (1)
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
CardioboostCm	Benign	0.0027
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		6.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.10
Sift	Benign	0.063	T
Sift4G	Benign	0.15	T
Polyphen		0.18	B
Vest4		0.76
MutPred		0.31		Gain of sheet (P = 0.0477)
MVP		0.80
MPC		0.26
ClinPred		0.57	D
GERP RS		4.1
Varity_R		0.096
gMVP		0.35
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.34
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 2
DS_DL_spliceai		0.37		Position offset: -2

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

Other links and lift over

dbSNP: rs397515993; hg19: chr11-47372792;