chr11-47337792-C-G

Variant names:

• chr11-47337792-C-G
• NM_000256.3:c.2311G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000256.3(MYBPC3):​c.2311G>C​(p.Val771Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000715 in 1,398,740 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V771M) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Ig-like C2-type 5 (size 126) in uniprot entity MYPC3_HUMAN there are 34 pathogenic changes around while only 4 benign (89%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47337792-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2311G>C	p.Val771Leu	missense_variant, splice_region_variant	Exon 24 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2311G>C	p.Val771Leu	missense_variant, splice_region_variant	Exon 24 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2311G>C	p.Val771Leu	missense_variant, splice_region_variant	Exon 23 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2311G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 24 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398740 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 689892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
CardioboostCm	Benign	0.011
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;T
Eigen	Benign	0.041
Eigen_PC	Benign	0.041
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Benign	0.13
Sift	Benign	0.11	T;.;T
Sift4G	Uncertain	0.030	D;D;D
Vest4		0.71
MVP		0.70
MPC		0.23
ClinPred		0.58	D
GERP RS		3.8
Varity_R		0.28
gMVP		0.73

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-47359343;