rs142620954

chr20-31823495-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_033118.4(MYLK2):c.791C>T(p.Pro264Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,613,344 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P264P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00071 (11 hom.)
• Consequence: MYLK2 NM_033118.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.99

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009515107).
• BP6: Variant 20-31823495-C-T is Benign according to our data. Variant chr20-31823495-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164504.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 235 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK2	NM_033118.4	c.791C>T	p.Pro264Leu	missense_variant	5/13	ENST00000375985.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK2	ENST00000375985.5	c.791C>T	p.Pro264Leu	missense_variant	5/13	1	NM_033118.4	P1
MYLK2	ENST00000375994.6	c.791C>T	p.Pro264Leu	missense_variant	4/12	1		P1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 235 AN: 152248 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00155 AC: 387 AN: 250306 Hom.: 6 AF XY: 0.00148 AC XY: 200 AN XY: 135416

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000710 AC: 1037 AN: 1460978 Hom.: 11 Cov.: 31 AF XY: 0.000666 AC XY: 484 AN XY: 726796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0164

Gnomad4 NFE exome AF: 0.000123

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152366 Hom.: 3 Cov.: 33 AF XY: 0.00217 AC XY: 162 AN XY: 74512

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00118 AC: 143

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 10, 2014

Variant classified as Uncertain Significance - Favor Benign. The Pro264Leu varia nt in MYLK2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/8600 European American chromosomes by the NHLBI Ex ome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs142620954). P roline (Pro) at position 264 is not conserved in evolutionarily distant species and 7 fish species carry a leucine (Leu) at this position, raising the possibili ty that this change may be tolerated. In summary, while the clinical significanc e of the Pro264Leu variant is uncertain, the presence of the variant amino acid in several species indicates it is more likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 26, 2018

- -

Hypertrophic cardiomyopathy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.0095	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.7	D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		0.97	D;D
Vest4		0.41
MVP		0.73
MPC		0.28
ClinPred		0.23	T
GERP RS		3.8
Varity_R		0.28
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs142620954; hg19: chr20-30411298; COSMIC: COSV65658543; COSMIC: COSV65658543;