rs199476406

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBS1BS2

The NM_032578.4(MYPN):c.1229T>C(p.Val410Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,614,008 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000053 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 1 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:2O:1

Conservation

PhyloP100: 2.38

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:

LOC107984240 (HGNC:):

LOC107984240 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40182686).

BP6

Variant 10-68148451-T-C is Benign according to our data. Variant chr10-68148451-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 31815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000525 (8/152358) while in subpopulation AMR AF= 0.000523 (8/15304). AF 95% confidence interval is 0.00026. There are 1 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4 linkuse as main transcript	c.1229T>C	p.Val410Ala	missense_variant	5/20	ENST00000358913.10
LOC107984240	XR_001747479.2 linkuse as main transcript	n.206-1733A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10 linkuse as main transcript	c.1229T>C	p.Val410Ala	missense_variant	5/20	1	NM_032578.4	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251342

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00121

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:

0.0000315

AC:

AN:

1461650

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000984

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:

0.0000166

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000523

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:

0.00

Bravo

AF:

0.0000491

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1KK

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	Jun 27, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Aug 07, 2023	- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2018

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. -

not provided

Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (MYPN)

Apr 27, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.080

Cadd

Benign

Dann

Benign

0.97

Eigen

Benign

-0.011

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.55

T;T;.;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.40

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

L;.;L;.;L

MutationTaster

Benign

0.96

N;N;N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.47

N;N;N;.;N

REVEL

Benign

0.21

Sift

Benign

0.64

T;T;T;.;T

Sift4G

Benign

0.70

T;T;T;T;T

Polyphen

0.039

B;B;B;.;P

Vest4

0.60

MutPred

0.64

Gain of disorder (P = 0.0344);.;Gain of disorder (P = 0.0344);.;Gain of disorder (P = 0.0344);

MVP

0.67

MPC

0.17

ClinPred

0.085

GERP RS

5.8

Varity_R

0.094

gMVP

0.30

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