rs145656924

chr20-31821473-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_033118.4(MYLK2):c.508G>A(p.Glu170Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,613,834 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: MYLK2 NM_033118.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.01

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048090816).
• BP6: Variant 20-31821473-G-A is Benign according to our data. Variant chr20-31821473-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-31821473-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 241 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK2	NM_033118.4	c.508G>A	p.Glu170Lys	missense_variant	4/13	ENST00000375985.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK2	ENST00000375985.5	c.508G>A	p.Glu170Lys	missense_variant	4/13	1	NM_033118.4	P1
MYLK2	ENST00000375994.6	c.508G>A	p.Glu170Lys	missense_variant	3/12	1		P1

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 241 AN: 152220 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00565

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.000398 AC: 100 AN: 251022 Hom.: 1 AF XY: 0.000272 AC XY: 37 AN XY: 135784

Gnomad AFR exome AF: 0.00579

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: 0.000163

GnomAD4 exome AF: 0.000152 AC: 222 AN: 1461496 Hom.: 1 Cov.: 32 AF XY: 0.000136 AC XY: 99 AN XY: 727044

Gnomad4 AFR exome AF: 0.00523

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152338 Hom.: 2 Cov.: 33 AF XY: 0.00150 AC XY: 112 AN XY: 74492

Gnomad4 AFR AF: 0.00561

Gnomad4 AMR AF: 0.000457

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

Alfa AF: 0.000320 Hom.: 1

Bravo AF: 0.00179

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000601 AC: 73

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2020	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 27, 2017	p.Glu170Lys in exon 4 of MYLK2: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (69/10226) of African chromoso mes, including 1 homozygote, by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs145656924) -

Hypertrophic cardiomyopathy 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 20, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.33	N
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.45	T;T
Polyphen		0.98	D;D
Vest4		0.35
MVP		0.73
MPC		0.19
ClinPred		0.018	T
GERP RS		4.5
Varity_R		0.087
gMVP		0.28

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: rs145656924; hg19: chr20-30409276; COSMIC: COSV65659939;