rs761266023

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_053025.4(MYLK):​c.5214G>T​(p.Lys1738Asn) 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 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYLK
NM_053025.4 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.296
Variant links:
Genes affected
MYLK (HGNC:7590): (myosin light chain kinase) This gene, a muscle member of the immunoglobulin gene superfamily, encodes myosin light chain kinase which is a calcium/calmodulin dependent enzyme. This kinase phosphorylates myosin regulatory light chains to facilitate myosin interaction with actin filaments to produce contractile activity. This gene encodes both smooth muscle and nonmuscle isoforms. In addition, using a separate promoter in an intron in the 3' region, it encodes telokin, a small protein identical in sequence to the C-terminus of myosin light chain kinase, that is independently expressed in smooth muscle and functions to stabilize unphosphorylated myosin filaments. A pseudogene is located on the p arm of chromosome 3. Four transcript variants that produce four isoforms of the calcium/calmodulin dependent enzyme have been identified as well as two transcripts that produce two isoforms of telokin. Additional variants have been identified but lack full length transcripts. [provided by RefSeq, Jul 2008]
MYLK-AS1 (HGNC:42440): (MYLK antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYLK. . Gene score misZ 1.1317 (greater than the threshold 3.09). Trascript score misZ 3.1503 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, connective tissue disorder, megacystis-microcolon-intestinal hypoperistalsis syndrome, aortic aneurysm, familial thoracic 7.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYLKNM_053025.4 linkuse as main transcriptc.5214G>T p.Lys1738Asn missense_variant 31/34 ENST00000360304.8 NP_444253.3
MYLK-AS1NR_038266.2 linkuse as main transcriptn.290-2652C>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYLKENST00000360304.8 linkuse as main transcriptc.5214G>T p.Lys1738Asn missense_variant 31/345 NM_053025.4 ENSP00000353452 P4Q15746-1
MYLK-AS1ENST00000485162.5 linkuse as main transcriptn.261-2652C>A intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461880
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 22, 2024The p.K1738N variant (also known as c.5214G>T), located in coding exon 28 of the MYLK gene, results from a G to T substitution at nucleotide position 5214. The lysine at codon 1738 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Benign
-0.032
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.53
.;.;.;D;.;D
Eigen
Benign
0.10
Eigen_PC
Benign
0.026
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.94
.;D;D;D;.;.
M_CAP
Benign
0.043
D
MetaRNN
Uncertain
0.46
T;T;T;T;T;T
MetaSVM
Benign
-0.43
T
MutationAssessor
Benign
2.0
.;.;.;M;.;M
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-3.3
D;.;D;D;D;D
REVEL
Benign
0.26
Sift
Benign
0.052
T;.;T;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;D
Vest4
0.62
MutPred
0.36
.;.;.;Loss of methylation at K1738 (P = 0.012);.;Loss of methylation at K1738 (P = 0.012);
MVP
0.86
MPC
1.0
ClinPred
0.85
D
GERP RS
0.28
Varity_R
0.21
gMVP
0.91

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs761266023; hg19: chr3-123345689; API