rs727504681

Positions:

• chr20-31820417-A-C

Variant summary

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

The ENST00000375985.5(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. 15/21 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 ENST00000375985.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.972

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=0.10257977).
• BS2: High AC in GnomAdExome4 at 23 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK2	NM_033118.4	c.344A>C	p.Gln115Pro	missense_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.344A>C	p.Gln115Pro	missense_variant	3/13	1	NM_033118.4	ENSP00000365152	P1
MYLK2	ENST00000375994.6	c.344A>C	p.Gln115Pro	missense_variant	2/12	1		ENSP00000365162	P1

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

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 17, 2014

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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 03, 2020

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 -

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	0.35	.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	N;N
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
Polyphen		0.0020	B;B
Vest4		0.35
MutPred		0.16		Gain of glycosylation at Q115 (P = 0.0532);Gain of glycosylation at Q115 (P = 0.0532);
MVP		0.75
MPC		0.11
ClinPred		0.097	T
GERP RS		4.7
Varity_R		0.076
gMVP		0.065

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504681; hg19: chr20-30408220;