3-123700840-G-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_053025.4(MYLK):​c.2628C>T​(p.Arg876Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000462 in 1,613,944 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R876R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00048 ( 4 hom. )

Consequence

MYLK
NM_053025.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.44

Publications

1 publications found
Variant links:
Genes affected
MYLK (HGNC:7590): (myosin light chain kinase) This gene, a muscle member of the immunoglobulin gene superfamily, encodes myosin light chain kinase which is a calcium/calmodulin dependent enzyme. This kinase phosphorylates myosin regulatory light chains to facilitate myosin interaction with actin filaments to produce contractile activity. This gene encodes both smooth muscle and nonmuscle isoforms. In addition, using a separate promoter in an intron in the 3' region, it encodes telokin, a small protein identical in sequence to the C-terminus of myosin light chain kinase, that is independently expressed in smooth muscle and functions to stabilize unphosphorylated myosin filaments. A pseudogene is located on the p arm of chromosome 3. Four transcript variants that produce four isoforms of the calcium/calmodulin dependent enzyme have been identified as well as two transcripts that produce two isoforms of telokin. Additional variants have been identified but lack full length transcripts. [provided by RefSeq, Jul 2008]
MYLK-AS1 (HGNC:42440): (MYLK antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.61).
BP6
Variant 3-123700840-G-A is Benign according to our data. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123700840-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 262278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-1.44 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000269 (41/152210) while in subpopulation SAS AF = 0.00788 (38/4820). AF 95% confidence interval is 0.0059. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYLKNM_053025.4 linkc.2628C>T p.Arg876Arg synonymous_variant Exon 18 of 34 ENST00000360304.8 NP_444253.3 Q15746-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYLKENST00000360304.8 linkc.2628C>T p.Arg876Arg synonymous_variant Exon 18 of 34 5 NM_053025.4 ENSP00000353452.3 Q15746-1

Frequencies

GnomAD3 genomes
AF:
0.000263
AC:
40
AN:
152092
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00767
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000908
AC:
228
AN:
251232
AF XY:
0.00121
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000482
AC:
704
AN:
1461734
Hom.:
4
Cov.:
40
AF XY:
0.000661
AC XY:
481
AN XY:
727174
show subpopulations
African (AFR)
AF:
0.0000896
AC:
3
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39700
South Asian (SAS)
AF:
0.00752
AC:
649
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53270
Middle Eastern (MID)
AF:
0.000347
AC:
2
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000180
AC:
20
AN:
1112004
Other (OTH)
AF:
0.000447
AC:
27
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
64
128
191
255
319
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000269
AC:
41
AN:
152210
Hom.:
0
Cov.:
31
AF XY:
0.000430
AC XY:
32
AN XY:
74400
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41528
American (AMR)
AF:
0.000131
AC:
2
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5152
South Asian (SAS)
AF:
0.00788
AC:
38
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2104
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.514
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000103
Hom.:
0
Bravo
AF:
0.0000642
Asia WGS
AF:
0.00231
AC:
8
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
-
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 24, 2016
Eurofins Ntd Llc (ga)
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aortic aneurysm, familial thoracic 7 Benign:2
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Dec 09, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1
Sep 14, 2016
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1
Jul 14, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.61
CADD
Benign
2.3
DANN
Benign
0.80
PhyloP100
-1.4
PromoterAI
0.054
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs571744275; hg19: chr3-123419687; COSMIC: COSV60615416; COSMIC: COSV60615416; API