rs727504559

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000432.4(MYL2):​c.421G>T​(p.Ala141Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

MYL2
NM_000432.4 missense

Scores

3
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.53
Variant links:
Genes affected
MYL2 (HGNC:7583): (myosin light chain 2) This gene encodes a major sarcomeric protein in mammalian striated muscle. The encoded protein plays a role in embryonic heart muscle structure and function, while phosphorylation of the encoded protein is involved in cardiac myosin cycling kinetics, torsion and function in adults. Mutations in this gene are associated with hypertrophic cardiomyopathy 10 and infant-onset myopathy. [provided by RefSeq, May 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a chain Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (size 164) in uniprot entity MLRV_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000432.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYL2NM_000432.4 linkuse as main transcriptc.421G>T p.Ala141Ser missense_variant 7/7 ENST00000228841.15 NP_000423.2
MYL2NM_001406745.1 linkuse as main transcriptc.379G>T p.Ala127Ser missense_variant 6/6 NP_001393674.1
MYL2NM_001406916.1 linkuse as main transcriptc.364G>T p.Ala122Ser missense_variant 7/7 NP_001393845.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYL2ENST00000228841.15 linkuse as main transcriptc.421G>T p.Ala141Ser missense_variant 7/71 NM_000432.4 ENSP00000228841 P1
MYL2ENST00000548438.1 linkuse as main transcriptc.379G>T p.Ala127Ser missense_variant 6/63 ENSP00000447154
MYL2ENST00000663220.1 linkuse as main transcriptc.364G>T p.Ala122Ser missense_variant 7/7 ENSP00000499568

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2023MYL2: PM2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
CardioboostCm
Benign
0.097
BayesDel_addAF
Uncertain
0.079
D
BayesDel_noAF
Benign
-0.12
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T;.
Eigen
Benign
-0.0053
Eigen_PC
Benign
0.15
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Benign
-0.57
T
MutationAssessor
Uncertain
2.0
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.4
N;N
REVEL
Uncertain
0.38
Sift
Benign
0.53
T;T
Sift4G
Benign
0.65
T;T
Polyphen
0.0080
B;.
Vest4
0.71
MutPred
0.54
Gain of catalytic residue at P143 (P = 0.0028);.;
MVP
0.86
MPC
0.74
ClinPred
0.96
D
GERP RS
5.0
Varity_R
0.37
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-111348961; API