chr10-68174320-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032578.4(MYPN):​c.2228C>T​(p.Pro743Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0002 in 1,614,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P743P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

9
10

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.21
Variant links:
Genes affected
MYPN (HGNC:23246): (myopalladin) Striated muscle in vertebrates comprises large proteins which must be organized properly to contract efficiently. Z-lines in striated muscle are a sign of this organization, representing the ends of actin thin filaments, titin, nebulin or nebulette and accessory proteins required for structure and function. This gene encodes a protein which interacts with nebulin in skeletal muscle or nebulette in cardiac muscle and alpha-actinin. In addition, this gene product can interact with a protein with the I-band indicating it has a regulatory as well as structural function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

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=0.010187715).
BP6
Variant 10-68174320-C-T is Benign according to our data. Variant chr10-68174320-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 201895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68174320-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000644 (98/152264) while in subpopulation AFR AF= 0.00212 (88/41544). AF 95% confidence interval is 0.00176. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 98 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYPNNM_032578.4 linkuse as main transcriptc.2228C>T p.Pro743Leu missense_variant 11/20 ENST00000358913.10 NP_115967.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYPNENST00000358913.10 linkuse as main transcriptc.2228C>T p.Pro743Leu missense_variant 11/201 NM_032578.4 ENSP00000351790.5 Q86TC9-1

Frequencies

GnomAD3 genomes
AF:
0.000638
AC:
97
AN:
152146
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00210
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000187
AC:
47
AN:
251300
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135812
show subpopulations
Gnomad AFR exome
AF:
0.00203
Gnomad AMR exome
AF:
0.000116
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:
0.0000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000154
AC:
225
AN:
1461882
Hom.:
0
Cov.:
74
AF XY:
0.000140
AC XY:
102
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00188
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000128
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000644
AC:
98
AN:
152264
Hom.:
0
Cov.:
31
AF XY:
0.000524
AC XY:
39
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.00212
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000166
Hom.:
0
Bravo
AF:
0.000861
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00318
AC:
14
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000231
AC:
28
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Likely benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesDec 14, 2020- -
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 11, 2021- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 24, 2014p.Pro743Leu in exon 12 of MYPN: This variant is not expected to have clinical si gnificance because it has been identified in 0.2% (23/10406) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs138583865). -
Dilated cardiomyopathy 1KK Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 14, 2018This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.10
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.052
.;.;.;T
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.87
D;D;.;D
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.010
T;T;T;T
MetaSVM
Benign
-0.73
T
MutationAssessor
Uncertain
2.2
M;.;M;.
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-1.9
N;N;N;.
REVEL
Benign
0.21
Sift
Uncertain
0.0030
D;D;D;.
Sift4G
Uncertain
0.0090
D;D;D;D
Polyphen
0.99
D;D;D;.
Vest4
0.21
MVP
0.75
MPC
0.14
ClinPred
0.051
T
GERP RS
5.8
Varity_R
0.13
gMVP
0.51

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: rs138583865; hg19: chr10-69934077; API