rs763971356

Variant names:

• chr20-31832095-C-G
• rs763971356
• NM_033118.4:c.1669C>G

Your query was ambiguous. Multiple possible variants found:

• chr20-31832095-C-G
• chr20-31832095-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033118.4(MYLK2):​c.1669C>G​(p.Gln557Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q557H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYLK2 NM_033118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37716833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK2	NM_033118.4	c.1669C>G	p.Gln557Glu	missense_variant	Exon 12 of 13	ENST00000375985.5	NP_149109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK2	ENST00000375985.5	c.1669C>G	p.Gln557Glu	missense_variant	Exon 12 of 13	1	NM_033118.4	ENSP00000365152.4
MYLK2	ENST00000375994.6	c.1669C>G	p.Gln557Glu	missense_variant	Exon 11 of 12	1		ENSP00000365162.2
MYLK2	ENST00000468730.1	n.607C>G		non_coding_transcript_exon_variant	Exon 5 of 6	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gln557Glu variant in MYLK2 has not been previously reported in individuals with cardiomyopathy and is absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gln557Glu variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	.;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		4.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.15
Sift	Benign	0.044	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.77	P;P
Vest4		0.33
MutPred		0.32		Gain of phosphorylation at S556 (P = 0.1257);Gain of phosphorylation at S556 (P = 0.1257);
MVP		0.75
MPC		0.46
ClinPred		0.93	D
GERP RS		4.9
Varity_R		0.26
gMVP		0.52
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs763971356; hg19: chr20-30419898;