rs142620954

Positions:

chr20-31823495-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_033118.4(MYLK2):c.791C>T(p.Pro264Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,613,344 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P264P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00071 ( 11 hom. )

Consequence

MYLK2
NM_033118.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.99

Variant links:

Genes affected

MYLK2 (HGNC:16243): (myosin light chain kinase 2) This gene encodes a myosin light chain kinase, a calcium/calmodulin dependent enzyme, that is exclusively expressed in adult skeletal muscle. [provided by RefSeq, Jul 2008]

MYLK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009515107).

BP6

Variant 20-31823495-C-T is Benign according to our data. Variant chr20-31823495-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164504.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.

BS2

High AC in GnomAd4 at 235 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK2	NM_033118.4 linkuse as main transcript	c.791C>T	p.Pro264Leu	missense_variant	5/13	ENST00000375985.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK2	ENST00000375985.5 linkuse as main transcript	c.791C>T	p.Pro264Leu	missense_variant	5/13	1	NM_033118.4	P1
MYLK2	ENST00000375994.6 linkuse as main transcript	c.791C>T	p.Pro264Leu	missense_variant	4/12	1		P1

Frequencies

GnomAD3 genomes

AF:

0.00154

AC:

235

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0183

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00155

AC:

387

AN:

250306

Hom.:

AF XY:

0.00148

AC XY:

200

AN XY:

135416

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0156

Gnomad NFE exome

AF:

0.000415

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000710

AC:

1037

AN:

1460978

Hom.:

Cov.:

AF XY:

0.000666

AC XY:

484

AN XY:

726796

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0164

Gnomad4 NFE exome

AF:

0.000123

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.00154

AC:

235

AN:

152366

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

162

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0183

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000434

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00118

AC:

143

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 10, 2014

Variant classified as Uncertain Significance - Favor Benign. The Pro264Leu varia nt in MYLK2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/8600 European American chromosomes by the NHLBI Ex ome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs142620954). P roline (Pro) at position 264 is not conserved in evolutionarily distant species and 7 fish species carry a leucine (Leu) at this position, raising the possibili ty that this change may be tolerated. In summary, while the clinical significanc e of the Pro264Leu variant is uncertain, the presence of the variant amino acid in several species indicates it is more likely benign. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 26, 2018

- -

Hypertrophic cardiomyopathy 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

D;D

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.90

.;D

MetaRNN

Benign

0.0095

T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

0.97

D;D

Vest4

0.41

MVP

0.73

MPC

0.28

ClinPred

0.23

GERP RS

3.8

Varity_R

0.28

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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