12-110911150-G-T

Variant summary

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

The NM_000432.4(MYL2):​c.428C>A​(p.Pro143His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYL2
NM_000432.4 missense

Scores

9
10
1

Clinical Significance

Not reported in ClinVar

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]

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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, 0.884

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYL2NM_000432.4 linkc.428C>A p.Pro143His missense_variant Exon 7 of 7 ENST00000228841.15 NP_000423.2 P10916Q6IB42
MYL2NM_001406745.1 linkc.386C>A p.Pro129His missense_variant Exon 6 of 6 NP_001393674.1
MYL2NM_001406916.1 linkc.371C>A p.Pro124His missense_variant Exon 7 of 7 NP_001393845.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYL2ENST00000228841.15 linkc.428C>A p.Pro143His missense_variant Exon 7 of 7 1 NM_000432.4 ENSP00000228841.8 P10916
MYL2ENST00000548438.1 linkc.386C>A p.Pro129His missense_variant Exon 6 of 6 3 ENSP00000447154.1 G3V1V8
MYL2ENST00000663220.1 linkc.371C>A p.Pro124His missense_variant Exon 7 of 7 ENSP00000499568.1 A0A590UJU8

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461690
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
CardioboostCm
Uncertain
0.34
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
D;.
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Uncertain
0.014
D
MutationAssessor
Uncertain
2.6
M;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-6.8
D;D
REVEL
Pathogenic
0.80
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.010
D;D
Polyphen
0.43
B;.
Vest4
0.83
MutPred
0.52
Gain of catalytic residue at A141 (P = 0.001);.;
MVP
0.92
MPC
0.92
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.82
gMVP
0.76

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: chr12-111348954; API