rs727505336
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_033118.4(MYLK2):c.1112T>C(p.Ile371Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
MYLK2
NM_033118.4 missense
NM_033118.4 missense
Scores
6
6
6
Clinical Significance
Conservation
PhyloP100: 7.89
Genes affected
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.865
BS2
?
High AC in GnomAdExome at 12 AD,Digenic gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK2 | NM_033118.4 | c.1112T>C | p.Ile371Thr | missense_variant | 8/13 | ENST00000375985.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK2 | ENST00000375985.5 | c.1112T>C | p.Ile371Thr | missense_variant | 8/13 | 1 | NM_033118.4 | P1 | |
MYLK2 | ENST00000375994.6 | c.1112T>C | p.Ile371Thr | missense_variant | 7/12 | 1 | P1 | ||
MYLK2 | ENST00000468730.1 | n.50T>C | non_coding_transcript_exon_variant | 1/6 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151978Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251392Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135874
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461882Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727236
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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 06, 2014 | The p.Ile371Thr variant MYLK2 has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 2/8766 East Asian chromosomes by t he Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org). Computat ional prediction tools and conservation analysis do not provide strong support f or or against an impact to the protein. In summary, the clinical significance of the p.Ile371Thr variant is uncertain. - |
Hypertrophic cardiomyopathy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYLK2 protein function. ClinVar contains an entry for this variant (Variation ID: 180083). This variant has not been reported in the literature in individuals affected with MYLK2-related conditions. This variant is present in population databases (rs727505336, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 371 of the MYLK2 protein (p.Ile371Thr). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
B;B
Vest4
MutPred
Gain of disorder (P = 0.0132);Gain of disorder (P = 0.0132);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at