rs25667

Positions:

• chr19-50464383-G-A
• chr19-50464383-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004533.4(MYBPC2):​c.3266G>A​(p.Arg1089His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,609,318 control chromosomes in the GnomAD database, including 30,503 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2310 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28193 hom.)
• Consequence: MYBPC2 NM_004533.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.547

Genes affected

MYBPC2 (HGNC:7550): (myosin binding protein C2) This gene encodes a member of the myosin-binding protein C family. This family includes the fast-, slow- and cardiac-type isoforms, each of which is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. The protein encoded by this locus is referred to as the fast-type isoform. Mutations in the related but distinct genes encoding the slow-type and cardiac-type isoforms have been associated with distal arthrogryposis, type 1 and hypertrophic cardiomyopathy, respectively. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031134486).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC2	NM_004533.4	c.3266G>A	p.Arg1089His	missense_variant	27/28	ENST00000357701.6	NP_004524.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC2	ENST00000357701.6	c.3266G>A	p.Arg1089His	missense_variant	27/28	1	NM_004533.4	ENSP00000350332.4
MYBPC2	ENST00000597498.1	n.153G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23729 AN: 152036 Hom.: 2310 Cov.: 32

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.199 AC: 48153 AN: 242206 Hom.: 5344 AF XY: 0.196 AC XY: 25717 AN XY: 131184

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.107

Gnomad SAS exome AF: 0.169

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.193 AC: 280679 AN: 1457164 Hom.: 28193 Cov.: 32 AF XY: 0.191 AC XY: 138654 AN XY: 724352

Gnomad4 AFR exome AF: 0.0356

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.193

Gnomad4 EAS exome AF: 0.136

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.206

Gnomad4 NFE exome AF: 0.195

Gnomad4 OTH exome AF: 0.189

GnomAD4 genome AF: 0.156 AC: 23728 AN: 152154 Hom.: 2310 Cov.: 32 AF XY: 0.159 AC XY: 11827 AN XY: 74380

Gnomad4 AFR AF: 0.0410

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.209

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.186

Alfa AF: 0.186 Hom.: 4213

Bravo AF: 0.157

TwinsUK AF: 0.206 AC: 764

ALSPAC AF: 0.206 AC: 792

ESP6500AA AF: 0.0406 AC: 171

ESP6500EA AF: 0.191 AC: 1622

ExAC AF: 0.193 AC: 23389

Asia WGS AF: 0.158 AC: 552 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.80
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.056
Sift	Benign	0.56	T
Sift4G	Benign	0.24	T
Polyphen		0.0020	B
Vest4		0.058
MPC		0.18
ClinPred		0.00079	T
GERP RS		-0.52
Varity_R		0.053
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs25667; hg19: chr19-50967640; COSMIC: COSV63095012; COSMIC: COSV63095012;