rs397517475

chr20-31823506-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033118.4(MYLK2):c.802C>T(p.Pro268Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,310 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P268L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYLK2 NM_033118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00100

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08881527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK2	NM_033118.4	c.802C>T	p.Pro268Ser	missense_variant	5/13	ENST00000375985.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK2	ENST00000375985.5	c.802C>T	p.Pro268Ser	missense_variant	5/13	1	NM_033118.4	P1
MYLK2	ENST00000375994.6	c.802C>T	p.Pro268Ser	missense_variant	4/12	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461310 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726974

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 14, 2012

Variant classified as Uncertain Significance - Favor Benign. The Pro268Ser varia nt in MYLK2 has not been reported in the literature nor previously identified by our laboratory or in large and broad European American and African American pop ulations screened by the NHLBI Exome Sequencing Project (http://evs.gs.washingto n.edu/EVS/). This low frequency is insufficient to assess its clinical significa nce. Proline (Pro) at position 268 is not conserved in evolution and two mammals (mega bat and opossum) carry the variant amino acid (serine) suggesting that it may be tolerated. In summary, this variant is less likely disease causing but a dditional studies are needed to fully assess its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	16
Dann	Benign	0.94
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.089	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.23	N;N
REVEL	Benign	0.057
Sift	Benign	0.16	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0010	B;B
Vest4		0.24
MutPred		0.28		Gain of phosphorylation at P268 (P = 0.0555);Gain of phosphorylation at P268 (P = 0.0555);
MVP		0.61
MPC		0.087
ClinPred		0.068	T
GERP RS		1.8
Varity_R		0.034
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397517475; hg19: chr20-30411309; COSMIC: COSV105314434; COSMIC: COSV105314434;