rs727504681

Variant names:

• chr20-31820417-A-C
• rs727504681
• NM_033118.4:c.344A>C

Your query was ambiguous. Multiple possible variants found:

• chr20-31820417-A-C
• chr20-31820417-A-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_033118.4(MYLK2):​c.344A>C​(p.Gln115Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,460,574 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (1 hom.)
• Consequence: MYLK2 NM_033118.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.972
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10257977).
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK2	NM_033118.4	c.344A>C	p.Gln115Pro	missense_variant	Exon 3 of 13	ENST00000375985.5	NP_149109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK2	ENST00000375985.5	c.344A>C	p.Gln115Pro	missense_variant	Exon 3 of 13	1	NM_033118.4	ENSP00000365152.4
MYLK2	ENST00000375994.6	c.344A>C	p.Gln115Pro	missense_variant	Exon 2 of 12	1		ENSP00000365162.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460574 Hom.: 1 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 726592

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111894

Other (OTH) AF: 0.0000994 AC: 6 AN: 60372

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.344A>C (p.Q115P) alteration is located in exon 3 (coding exon 2) of the MYLK2 gene. This alteration results from a A to C substitution at nucleotide position 344, causing the glutamine (Q) at amino acid position 115 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Dec 17, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Gln115Pro var iant in MYLK2 has been identified by our laboratory in 1 individual with bi-atri al and right ventricle dilation and EKG abnormalities who also carried another d isease causing variant in another gene. It was absent from large population stud ies. Glutamine (Gln) at position 115 is not conserved in evolution and Chinese h amster, golden hamster, and cape golden mole have a proline (Pro) at this positi on, raising the possibility that this change may be tolerated. Additional comput ational analyses do not provide strong support for or against an impact to the p rotein. In summary, while the clinical significance of the p.Gln115Pro variant i s uncertain, the presence of the variant amino acid in other mammals suggests th at it is more likely to be benign.

not provided Uncertain:1

Feb 03, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 179165; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function

Hypertrophic cardiomyopathy 1 Uncertain:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 115 of the MYLK2 protein (p.Gln115Pro). This variant is not present in population databases (gnomAD no frequency). 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: 179165). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYLK2 protein function with a negative predictive value of 80%. 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	0.053
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.1
DANN	Benign	0.55
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.0	.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		0.97
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.88	N;N
REVEL	Benign	0.13
Sift	Benign	0.11	T;T
Sift4G	Benign	0.27	T;T
Vest4		0.35
ClinPred		0.097	T
GERP RS		4.7
Varity_R		0.076
gMVP		0.065
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727504681; hg19: chr20-30408220;