rs1555257600

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000432.4(MYL2):​c.427C>A​(p.Pro143Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,952 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 0.0000066 ( 0 hom., cov: 31)

Consequence

MYL2
NM_000432.4 missense

Scores

11
6
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.55
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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, 0.888

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYL2NM_000432.4 linkuse as main transcriptc.427C>A p.Pro143Thr missense_variant 7/7 ENST00000228841.15 NP_000423.2 P10916Q6IB42
MYL2NM_001406745.1 linkuse as main transcriptc.385C>A p.Pro129Thr missense_variant 6/6 NP_001393674.1
MYL2NM_001406916.1 linkuse as main transcriptc.370C>A p.Pro124Thr 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.427C>A p.Pro143Thr missense_variant 7/71 NM_000432.4 ENSP00000228841.8 P10916
MYL2ENST00000548438.1 linkuse as main transcriptc.385C>A p.Pro129Thr missense_variant 6/63 ENSP00000447154.1 G3V1V8
MYL2ENST00000663220.1 linkuse as main transcriptc.370C>A p.Pro124Thr missense_variant 7/7 ENSP00000499568.1 A0A590UJU8

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151952
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151952
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74204
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 10 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 28, 2022In 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 532776). This variant has not been reported in the literature in individuals affected with MYL2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 143 of the MYL2 protein (p.Pro143Thr). -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsApr 21, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
CardioboostCm
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
D;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Uncertain
0.34
D
MutationAssessor
Uncertain
2.1
M;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-5.5
D;D
REVEL
Pathogenic
0.81
Sift
Benign
0.065
T;T
Sift4G
Uncertain
0.060
T;T
Polyphen
0.99
D;.
Vest4
0.81
MutPred
0.52
Gain of catalytic residue at A141 (P = 5e-04);.;
MVP
0.93
MPC
1.3
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.64
gMVP
0.74

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

LitVar

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

Other links and lift over

dbSNP: rs1555257600; hg19: chr12-111348955; API