chr20-31819630-C-A

Position:

chr20-31819630-C-A

Variant summary

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

The NM_033118.4(MYLK2):c.50C>A(p.Thr17Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,551,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T17I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MYLK2
NM_033118.4 missense, splice_region

Scores

Splicing: ADA: 0.8156

Clinical Significance

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

Conservation

PhyloP100: 0.556

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=0.008819342).

BP6

Variant 20-31819630-C-A is Benign according to our data. Variant chr20-31819630-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 338040.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 19 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK2	NM_033118.4 linkuse as main transcript	c.50C>A	p.Thr17Lys	missense_variant, splice_region_variant	2/13	ENST00000375985.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK2	ENST00000375985.5 linkuse as main transcript	c.50C>A	p.Thr17Lys	missense_variant, splice_region_variant	2/13	1	NM_033118.4	P1
MYLK2	ENST00000375994.6 linkuse as main transcript	c.50C>A	p.Thr17Lys	missense_variant, splice_region_variant	1/12	1		P1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00367

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:

0.000109

AC:

AN:

156422

Hom.:

AF XY:

0.0000972

AC XY:

AN XY:

82276

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00150

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:

0.000135

AC:

189

AN:

1399264

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

690114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00520

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000517

GnomAD4 genome

AF:

0.000125

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00368

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000854

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000362

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 17, 2022	The p.T17K variant (also known as c.50C>A), located in coding exon 1 of the MYLK2 gene, results from a C to A substitution at nucleotide position 50. The threonine at codon 17 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. 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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 21, 2023

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 17 of the MYLK2 protein (p.Thr17Lys). This variant is present in population databases (rs192056427, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYLK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 338040). 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 disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

0.017

Eigen_PC

Benign

0.038

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.51

.;T

M_CAP

Benign

0.075

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

0.92

D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.10

N;N

REVEL

Benign

0.079

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

0.74

P;P

Vest4

0.26

MVP

0.74

MPC

0.29

ClinPred

0.20

GERP RS

3.5

Varity_R

0.15

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.82

dbscSNV1_RF

Benign

0.44

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