rs56056823

chr3-123640360-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_053025.4(MYLK):c.4764G>A(p.Pro1588=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00712 in 1,613,974 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0074 (45 hom.)
• Consequence: MYLK NM_053025.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.09

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)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-123640360-C-T is Benign according to our data. Variant chr3-123640360-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 196142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-123640360-C-T is described in Lovd as [Benign]. Variant chr3-123640360-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00489 (743/152086) while in subpopulation NFE AF= 0.00844 (574/67996). AF 95% confidence interval is 0.00787. There are 7 homozygotes in gnomad4. There are 327 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYLK	NM_053025.4	c.4764G>A	p.Pro1588=	synonymous_variant	28/34	ENST00000360304.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYLK	ENST00000360304.8	c.4764G>A	p.Pro1588=	synonymous_variant	28/34	5	NM_053025.4	P4
MYLK-AS1	ENST00000485162.5	n.523-4144C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 743 AN: 151968 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000835

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00844

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00448 AC: 1126 AN: 251474 Hom.: 6 AF XY: 0.00433 AC XY: 589 AN XY: 135908

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00773

Gnomad OTH exome AF: 0.00537

GnomAD4 exome AF: 0.00736 AC: 10756 AN: 1461888 Hom.: 45 Cov.: 32 AF XY: 0.00716 AC XY: 5210 AN XY: 727246

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.00195

Gnomad4 NFE exome AF: 0.00895

Gnomad4 OTH exome AF: 0.00644

GnomAD4 genome AF: 0.00489 AC: 743 AN: 152086 Hom.: 7 Cov.: 31 AF XY: 0.00440 AC XY: 327 AN XY: 74344

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000835

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00844

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00677 Hom.: 4

Bravo AF: 0.00487

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00774

EpiControl AF: 0.00705

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 02, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MYLK: BP4, BP7, BS2 -

Aortic aneurysm, familial thoracic 7 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 13, 2015	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. -

Aortic aneurysm, familial thoracic 7;C5542316:Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	8.2
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs56056823; hg19: chr3-123359207;