12-56160629-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_021019.5(MYL6):ā€‹c.431T>Cā€‹(p.Phe144Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000582 in 1,614,214 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 (ā˜…).

Frequency

Genomes: š‘“ 0.000072 ( 0 hom., cov: 32)
Exomes š‘“: 0.000057 ( 0 hom. )

Consequence

MYL6
NM_021019.5 missense

Scores

9
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.95
Variant links:
Genes affected
MYL6 (HGNC:7587): (myosin light chain 6) Myosin is a hexameric ATPase cellular motor protein. It is composed of two heavy chains, two nonphosphorylatable alkali light chains, and two phosphorylatable regulatory light chains. This gene encodes a myosin alkali light chain that is expressed in smooth muscle and non-muscle tissues. Genomic sequences representing several pseudogenes have been described and two transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYL6NM_021019.5 linkc.431T>C p.Phe144Ser missense_variant 6/7 ENST00000550697.6 NP_066299.2 P60660-1
MYL6NM_079423.4 linkc.427+309T>C intron_variant NP_524147.2 P60660-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYL6ENST00000550697.6 linkc.431T>C p.Phe144Ser missense_variant 6/71 NM_021019.5 ENSP00000446955.2 P60660-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000557
AC:
14
AN:
251458
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000114
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000568
AC:
83
AN:
1461878
Hom.:
0
Cov.:
31
AF XY:
0.0000550
AC XY:
40
AN XY:
727246
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:
0.0000746
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152336
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000789
Hom.:
0
Bravo
AF:
0.0000604
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 02, 2021The c.431T>C (p.F144S) alteration is located in exon 6 (coding exon 6) of the MYL6 gene. This alteration results from a T to C substitution at nucleotide position 431, causing the phenylalanine (F) at amino acid position 144 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.65
D;D;D;D
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.93
.;D;D;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.96
D;D;D;D
MetaSVM
Uncertain
0.69
D
MutationAssessor
Pathogenic
3.7
H;.;.;H
PROVEAN
Pathogenic
-5.5
D;D;D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.026
D;D;D;D
Sift4G
Uncertain
0.015
D;D;D;D
Polyphen
0.057
B;.;.;B
Vest4
0.94
MVP
0.99
MPC
0.84
ClinPred
0.48
T
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.57
gMVP
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs147680006; hg19: chr12-56554413; API