rs28763880

Positions:

• chr20-31820175-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_033118.4(MYLK2):​c.102A>G​(p.Lys34Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,614,032 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (12 hom.)
• Consequence: MYLK2 NM_033118.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.122

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 20-31820175-A-G is Benign according to our data. Variant chr20-31820175-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 46516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-31820175-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.122 with no splicing effect.
• BS2: High AC in GnomAd4 at 159 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK2	NM_033118.4	c.102A>G	p.Lys34Lys	synonymous_variant	3/13	ENST00000375985.5	NP_149109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK2	ENST00000375985.5	c.102A>G	p.Lys34Lys	synonymous_variant	3/13	1	NM_033118.4	ENSP00000365152.4
MYLK2	ENST00000375994.6	c.102A>G	p.Lys34Lys	synonymous_variant	2/12	1		ENSP00000365162.2

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00102 AC: 255 AN: 250470 Hom.: 4 AF XY: 0.00117 AC XY: 159 AN XY: 135502

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00172 AC: 2518 AN: 1461710 Hom.: 12 Cov.: 32 AF XY: 0.00175 AC XY: 1276 AN XY: 727148

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00246

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.00188

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74482

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00104

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 07, 2016	p.Lys34Lys in exon 3 of MYLK2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 0.2% (36/16510) of South Asian chromosomes including 2 homozygous individuals by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs28763880). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 30, 2022	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 28, 2021	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	MYLK2: BP4, BP7, BS2 -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 11, 2018

- -

Hypertrophic cardiomyopathy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.5
DANN	Benign	0.49

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: rs28763880; hg19: chr20-30407978; COSMIC: COSV65658957;