rs3817552

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002465.4(MYBPC1):c.1518C>G(p.His506Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,664 control chromosomes in the GnomAD database, including 20,958 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1815 hom., cov: 32)

Exomes 𝑓: 0.16 ( 19143 hom. )

Consequence

MYBPC1
NM_002465.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.45

Variant links:

Genes affected

MYBPC1 (HGNC:7549): (myosin binding protein C1) This gene encodes a member of the myosin-binding protein C family. Myosin-binding protein C family members are myosin-associated proteins found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. The encoded protein is the slow skeletal muscle isoform of myosin-binding protein C and plays an important role in muscle contraction by recruiting muscle-type creatine kinase to myosin filaments. Mutations in this gene are associated with distal arthrogryposis type I. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

MYBPC1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017406046).

BP6

Variant 12-101651385-C-G is Benign according to our data. Variant chr12-101651385-C-G is described in ClinVar as [Benign]. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC1	NM_002465.4 linkuse as main transcript	c.1518C>G	p.His506Gln	missense_variant	16/32	ENST00000361466.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC1	ENST00000361466.7 linkuse as main transcript	c.1518C>G	p.His506Gln	missense_variant	16/32	1	NM_002465.4	A2	Q00872-4
	ENST00000547027.1 linkuse as main transcript	n.258-4357G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.148

AC:

22569

AN:

151980

Hom.:

1814

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.105

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.299

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.155

Gnomad OTH

AF:

0.155

GnomAD3 exomes

AF:

0.156

AC:

39160

AN:

251400

Hom.:

3474

AF XY:

0.159

AC XY:

21640

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.126

Gnomad AMR exome

AF:

0.0803

Gnomad ASJ exome

AF:

0.190

Gnomad EAS exome

AF:

0.293

Gnomad SAS exome

AF:

0.154

Gnomad FIN exome

AF:

0.162

Gnomad NFE exome

AF:

0.157

Gnomad OTH exome

AF:

0.159

GnomAD4 exome

AF:

0.158

AC:

230827

AN:

1461566

Hom.:

19143

Cov.:

AF XY:

0.158

AC XY:

115165

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.119

Gnomad4 AMR exome

AF:

0.0836

Gnomad4 ASJ exome

AF:

0.187

Gnomad4 EAS exome

AF:

0.303

Gnomad4 SAS exome

AF:

0.155

Gnomad4 FIN exome

AF:

0.160

Gnomad4 NFE exome

AF:

0.156

Gnomad4 OTH exome

AF:

0.161

GnomAD4 genome

AF:

0.148

AC:

22562

AN:

152098

Hom.:

1815

Cov.:

AF XY:

0.149

AC XY:

11102

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.127

Gnomad4 AMR

AF:

0.105

Gnomad4 ASJ

AF:

0.189

Gnomad4 EAS

AF:

0.299

Gnomad4 SAS

AF:

0.160

Gnomad4 FIN

AF:

0.166

Gnomad4 NFE

AF:

0.155

Gnomad4 OTH

AF:

0.154

Alfa

AF:

0.149

Hom.:

1438

Bravo

AF:

0.144

TwinsUK

AF:

0.152

AC:

562

ALSPAC

AF:

0.154

AC:

593

ESP6500AA

AF:

0.130

AC:

571

ESP6500EA

AF:

0.148

AC:

1273

ExAC

AF:

0.157

AC:

19070

Asia WGS

AF:

0.204

AC:

708

AN:

3478

EpiCase

AF:

0.160

EpiControl

AF:

0.163

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Arthrogryposis, distal, type 1B

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Myopathy, congenital, with tremor

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Lethal congenital contracture syndrome 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2019

This variant is associated with the following publications: (PMID: 17000706, 23873045) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0017

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.00016

P;P;P;P;P;P;P;P;P;P;P;P;P;P;P

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.6

D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.012

D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;D;D;D;.;.;.;.;.;D

Vest4

0.45

MutPred

0.67

.;.;.;.;.;Gain of catalytic residue at R497 (P = 0.0011);.;.;.;.;.;.;.;

MPC

0.76

ClinPred

0.039

GERP RS

3.6

Varity_R

0.58

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over