rs201983087

Positions:

chr10-68122195-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_032578.4(MYPN):c.757G>C(p.Gly253Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,609,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 5.01

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]

MYPN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15354842).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000788 (12/152322) while in subpopulation NFE AF= 0.000147 (10/68034). AF 95% confidence interval is 0.0000791. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYPN	NM_032578.4 linkuse as main transcript	c.757G>C	p.Gly253Arg	missense_variant	2/20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10 linkuse as main transcript	c.757G>C	p.Gly253Arg	missense_variant	2/20	1	NM_032578.4	ENSP00000351790	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000688

AC:

AN:

247048

Hom.:

AF XY:

0.0000674

AC XY:

AN XY:

133450

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.000210

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000113

AC:

165

AN:

1457210

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

724516

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.000350

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000132

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2019	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 27, 2022	The MYPN c.757G>C; p.Gly253Arg variant (rs201983087), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 222748). This variant is found in the non-Finnish European population with an allele frequency of 0.011% (14/127,482 alleles) in the Genome Aggregation Database. The glycine at codon 253 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.11). Due to limited information, the clinical significance of the p.Gly253Arg variant is uncertain at this time. -

Left ventricular noncompaction cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 05, 2015

- -

Dilated cardiomyopathy 1KK

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 253 of the MYPN protein (p.Gly253Arg). This variant is present in population databases (rs201983087, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYPN-related conditions. ClinVar contains an entry for this variant (Variation ID: 222748). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2022

The p.G253R variant (also known as c.757G>C), located in coding exon 1 of the MYPN gene, results from a G to C substitution at nucleotide position 757. The glycine at codon 253 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1KK;C4479186:MYPN-related myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.86

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

T;.;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.2

L;L;L

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.40

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.43

T;T;T

Polyphen

0.81

P;P;P

Vest4

0.44

MutPred

0.21

Loss of glycosylation at S257 (P = 0.1477);Loss of glycosylation at S257 (P = 0.1477);Loss of glycosylation at S257 (P = 0.1477);

MVP

0.78

MPC

0.17

ClinPred

0.13

GERP RS

5.7

Varity_R

0.17

gMVP

0.39

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.

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