rs1002989047

Variant names:

• chr3-123732932-C-A
• rs1002989047
• NM_053025.4:c.1480G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-123732932-C-A
• chr3-123732932-C-G
• chr3-123732932-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_053025.4(MYLK):​c.1480G>T​(p.Gly494Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G494S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.87
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• aortic aneurysm, familial thoracic 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• megacystis-microcolon-intestinal hypoperistalsis syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: G2P
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• megacystis-microcolon-intestinal hypoperistalsis syndrome

  Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053025.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	NM_053025.4	MANE Select	c.1480G>T	p.Gly494Cys	missense	Exon 11 of 34	NP_444253.3
	MYLK	NM_053027.4		c.1480G>T	p.Gly494Cys	missense	Exon 11 of 33	NP_444255.3
	MYLK	NM_001321309.2		c.952G>T	p.Gly318Cys	missense	Exon 10 of 33	NP_001308238.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	ENST00000360304.8	TSL:5 MANE Select	c.1480G>T	p.Gly494Cys	missense	Exon 11 of 34	ENSP00000353452.3
	MYLK	ENST00000464489.5	TSL:1	n.*1059G>T		non_coding_transcript_exon	Exon 10 of 33	ENSP00000417798.1
	MYLK	ENST00000464489.5	TSL:1	n.*1059G>T		3_prime_UTR	Exon 10 of 33	ENSP00000417798.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		5.9
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.95		Loss of disorder (P = 0.0348)
MVP		0.90
MPC		0.64
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.91
gMVP		0.77
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1002989047; hg19: chr3-123451779;