rs397517473

Variant names:

• chr20-31820350-C-A
• rs397517473
• NM_033118.4:c.277C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-31820350-C-A
• chr20-31820350-C-G
• chr20-31820350-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_033118.4(MYLK2):​c.277C>A​(p.Pro93Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P93P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MYLK2 NM_033118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.454
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044395447).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK2	NM_033118.4	c.277C>A	p.Pro93Thr	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.277C>A	p.Pro93Thr	missense_variant	Exon 3 of 13	1	NM_033118.4	ENSP00000365152.4
MYLK2	ENST00000375994.6	c.277C>A	p.Pro93Thr	missense_variant	Exon 2 of 12	1		ENSP00000365162.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000203 AC: 5 AN: 246290 AF XY: 0.0000224

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460396 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726470

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52296

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111784

Other (OTH) AF: 0.0000331 AC: 2 AN: 60348

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2012

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 Pro93Thr varian t in MYLK2 has not been reported in the literature nor previously identified by our laboratory. Proline (Pro) at position 93 is not conserved in mammals, despit e high nearby amino acid conservation. Computational analyses (biochemical amino acid properties, AlignGVGD, and SIFT) suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathog enicity. Although the lack of conservation and computational tools suggest that the Pro93Thr variant may be benign, additional studies are needed to fully asses s its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.66	.;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L
PhyloP100		0.45
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.054
Sift	Uncertain	0.015	D;D
Sift4G	Benign	0.49	T;T
Polyphen		0.016	B;B
Vest4		0.13
MutPred		0.17		Gain of phosphorylation at P93 (P = 0.0108);Gain of phosphorylation at P93 (P = 0.0108);
MVP		0.53
MPC		0.10
ClinPred		0.023	T
GERP RS		1.6
Varity_R		0.076
gMVP		0.038
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs397517473; hg19: chr20-30408153;