rs6089088

Positions:

• chr20-31826818-C-A
• chr20-31826818-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033118.4(MYLK2):​c.1104C>A​(p.Phe368Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F368F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYLK2 NM_033118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.247

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK2	NM_033118.4	c.1104C>A	p.Phe368Leu	missense_variant	8/13	ENST00000375985.5	NP_149109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK2	ENST00000375985.5	c.1104C>A	p.Phe368Leu	missense_variant	8/13	1	NM_033118.4	ENSP00000365152	P1
MYLK2	ENST00000375994.6	c.1104C>A	p.Phe368Leu	missense_variant	7/12	1		ENSP00000365162	P1
MYLK2	ENST00000468730.1	n.42C>A		non_coding_transcript_exon_variant	1/6	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T
Eigen	Benign	-0.010
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.61	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Benign	0.28
Sift	Benign	0.032	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.88	P;P
Vest4		0.81
MutPred		0.71		Gain of helix (P = 0.2684);Gain of helix (P = 0.2684);
MVP		0.64
MPC		0.26
ClinPred		0.79	D
GERP RS		1.4
Varity_R		0.64
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: -21

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

Publications

LitVar

Other links and lift over

dbSNP: rs6089088; hg19: chr20-30414621;