19-50437522-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3 BP6_Moderate BS2

The NM_004533.4(MYBPC2):c.512+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.000312 in 1,610,090 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: MYBPC2 NM_004533.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.88

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 Likely_benign. Variant got -5 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, BayesDel_noAF, MutationTaster was below the threshold]
• BP6: Variant 19-50437522-G-A is Benign according to our data. Variant chr19-50437522-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3053488.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC2	NM_004533.4	c.512+1G>A		splice_donor_variant		ENST00000357701.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC2	ENST00000357701.6	c.512+1G>A		splice_donor_variant		1	NM_004533.4	P1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152114 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00565

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000430 AC: 104 AN: 241766 Hom.: 0 AF XY: 0.000290 AC XY: 38 AN XY: 130980

Gnomad AFR exome AF: 0.00599

Gnomad AMR exome AF: 0.000208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000640

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000170 AC: 248 AN: 1457858 Hom.: 2 Cov.: 32 AF XY: 0.000137 AC XY: 99 AN XY: 724784

Gnomad4 AFR exome AF: 0.00574

Gnomad4 AMR exome AF: 0.000250

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.00168 AC: 255 AN: 152232 Hom.: 2 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74418

Gnomad4 AFR AF: 0.00564

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000339 Hom.: 0

Bravo AF: 0.00183

ESP6500AA AF: 0.00655 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000505 AC: 61

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MYBPC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	30
Dann	Uncertain	0.98
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.85	D
MutationTaster	Benign	1.0	D
GERP RS		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs192680999; hg19: chr19-50940779; COSMIC: COSV63096421;