12-101631701-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_002465.4(MYBPC1):​c.420C>T​(p.Thr140Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,614,170 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0028 ( 12 hom. )

Consequence

MYBPC1
NM_002465.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0450
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
Variant 12-101631701-C-T is Benign according to our data. Variant chr12-101631701-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101631701-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.045 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00181 (276/152352) while in subpopulation NFE AF= 0.00329 (224/68042). AF 95% confidence interval is 0.00294. There are 1 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 12 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYBPC1NM_002465.4 linkuse as main transcriptc.420C>T p.Thr140Thr synonymous_variant 7/32 ENST00000361466.7 NP_002456.2 Q00872-4Q86TA8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYBPC1ENST00000361466.7 linkuse as main transcriptc.420C>T p.Thr140Thr synonymous_variant 7/321 NM_002465.4 ENSP00000354849.2 Q00872-4
MYBPC1ENST00000551300.5 linkuse as main transcriptc.48C>T p.Thr16Thr synonymous_variant 8/321 ENSP00000447116.1 G3V1V7

Frequencies

GnomAD3 genomes
AF:
0.00181
AC:
276
AN:
152234
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00329
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00121
AC:
305
AN:
251382
Hom.:
0
AF XY:
0.00128
AC XY:
174
AN XY:
135882
show subpopulations
Gnomad AFR exome
AF:
0.00117
Gnomad AMR exome
AF:
0.000260
Gnomad ASJ exome
AF:
0.00169
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.000277
Gnomad NFE exome
AF:
0.00216
Gnomad OTH exome
AF:
0.000815
GnomAD4 exome
AF:
0.00278
AC:
4068
AN:
1461818
Hom.:
12
Cov.:
32
AF XY:
0.00277
AC XY:
2011
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.000627
Gnomad4 AMR exome
AF:
0.000358
Gnomad4 ASJ exome
AF:
0.00107
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.000187
Gnomad4 NFE exome
AF:
0.00345
Gnomad4 OTH exome
AF:
0.00240
GnomAD4 genome
AF:
0.00181
AC:
276
AN:
152352
Hom.:
1
Cov.:
33
AF XY:
0.00161
AC XY:
120
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.000962
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00329
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00222
Hom.:
0
Bravo
AF:
0.00179
EpiCase
AF:
0.00234
EpiControl
AF:
0.00243

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2022MYBPC1: BP4, BP7 -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 05, 2021- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2019- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Arthrogryposis, distal, type 1B Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.46
CADD
Benign
2.8
DANN
Benign
0.60

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

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

Other links and lift over

dbSNP: rs140667525; hg19: chr12-102025479; API