rs397517472
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_033118.4(MYLK2):c.1123G>A(p.Asp375Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000115 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
MYLK2
NM_033118.4 missense
NM_033118.4 missense
Scores
2
16
Clinical Significance
Conservation
PhyloP100: 4.32
Genes affected
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.12573949).
BP6
?
Variant 20-31826837-G-A is Benign according to our data. Variant chr20-31826837-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46519.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr20-31826837-G-A is described in Lovd as [Likely_benign].
BS2
?
High AC in GnomAd4 at 9 AD,Digenic gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYLK2 | NM_033118.4 | c.1123G>A | p.Asp375Asn | missense_variant | 8/13 | ENST00000375985.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYLK2 | ENST00000375985.5 | c.1123G>A | p.Asp375Asn | missense_variant | 8/13 | 1 | NM_033118.4 | P1 | |
MYLK2 | ENST00000375994.6 | c.1123G>A | p.Asp375Asn | missense_variant | 7/12 | 1 | P1 | ||
MYLK2 | ENST00000468730.1 | n.61G>A | non_coding_transcript_exon_variant | 1/6 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152152Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000795 AC: 20AN: 251422Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135896
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GnomAD4 exome AF: 0.000120 AC: 176AN: 1461880Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 78AN XY: 727236
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GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152152Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74322
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
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 | Mar 30, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Asp375Asn var iant in MYLK2 has been identified by our laboratory in 1 adult with DCM, AFib, a nd VT who also carried a likely pathogenic variant in another DCM-associated gen e. This variant has been identified in 7/66650 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397517472 ). Aspartic acid (Asp) at position 375 is not conserved in evolutionarily distan t species, and 2 reptiles along with >10 fish species carry an asparagine (Asn) at this position. Additional computational prediction tools suggest that this va riant may not impact the protein, though this information is not predictive enou gh to rule out pathogenicity. In summary, while the clinical significance of the p.Asp375Asn variant is uncertain, the presence of the variant amino acid in mul tiple other species suggests that it is more likely to be benign. - |
Hypertrophic cardiomyopathy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 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 not expected to disrupt MYLK2 protein function. ClinVar contains an entry for this variant (Variation ID: 46519). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257). This variant is present in population databases (rs397517472, gnomAD 0.02%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 375 of the MYLK2 protein (p.Asp375Asn). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 24503780) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
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