rs145142157

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032578.4(MYPN):c.65C>G(p.Ala22Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,614,178 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 7.21

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]

MYPN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03400734).

BP6

Variant 10-68121503-C-G is Benign according to our data. Variant chr10-68121503-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229037.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr10-68121503-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000755 (115/152318) while in subpopulation AFR AF= 0.00269 (112/41578). AF 95% confidence interval is 0.00229. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 115 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4 linkuse as main transcript	c.65C>G	p.Ala22Gly	missense_variant	2/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10 linkuse as main transcript	c.65C>G	p.Ala22Gly	missense_variant	2/20	1	NM_032578.4	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251362

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.000145

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00242

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000755

AC:

115

AN:

152318

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00269

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:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000630

Hom.:

Bravo

AF:

0.000827

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000198

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 13, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Ala22Gly vari ant in MYPN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.2% (23/10358) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145142157) . Computational prediction tools and conservation analysis suggest that the p.Al a22Gly variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Ala22Gly variant is uncertain, its frequency suggests that it is more l ikely to be benign. -

Dilated cardiomyopathy 1KK

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2019

This 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.86

D;.;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.034

T;T;T

MetaSVM

Uncertain

0.057

MutationAssessor

Benign

2.0

M;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.63

N;N;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.014

D;D;D

Sift4G

Benign

0.10

T;T;D

Polyphen

1.0

D;D;D

Vest4

0.69

MVP

0.90

MPC

0.61

ClinPred

0.067

GERP RS

6.0

Varity_R

0.25

gMVP

0.56

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