rs139331477

chr20-31832126-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_033118.4(MYLK2):c.1700G>A(p.Arg567Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000054 in 1,609,974 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R567G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: MYLK2 NM_033118.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.76

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.088003695).
• BS2: High AC in GnomAd at 9 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK2	NM_033118.4	c.1700G>A	p.Arg567Lys	missense_variant	12/13	ENST00000375985.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK2	ENST00000375985.5	c.1700G>A	p.Arg567Lys	missense_variant	12/13	1	NM_033118.4	P1
MYLK2	ENST00000375994.6	c.1700G>A	p.Arg567Lys	missense_variant	11/12	1		P1
MYLK2	ENST00000468730.1	n.638G>A		non_coding_transcript_exon_variant	5/6	1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000702 AC: 17 AN: 242118 Hom.: 0 AF XY: 0.0000612 AC XY: 8 AN XY: 130644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00143

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000535 AC: 78 AN: 1457802 Hom.: 0 Cov.: 39 AF XY: 0.0000566 AC XY: 41 AN XY: 724564

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00196

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hypertrophic cardiomyopathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 567 of the MYLK2 protein (p.Arg567Lys). This variant is present in population databases (rs139331477, 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: 191741). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.088	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.17
Sift	Benign	0.094	T;T
Sift4G	Benign	0.082	T;T
Polyphen		0.77	P;P
Vest4		0.37
MVP		0.74
MPC		0.47
ClinPred		0.29	T
GERP RS		4.2
Varity_R		0.43
gMVP		0.79

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

Other links and lift over

dbSNP: rs139331477; hg19: chr20-30419929;