rs1553787823

Variant names:

• chr3-123664245-T-TCGCTTTC
• rs1553787823
• NM_053025.4:c.3838_3844dupGAAAGCG

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PVS1 PS3 PM2 PP5

The NM_053025.4(MYLK):​c.3838_3844dupGAAAGCG​(p.Glu1282GlyfsTer51) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). ClinVar reports functional evidence for this variant: "SCV000299345: Loss of protein. Functional experiments described in manuscript.". Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYLK NM_053025.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.75
• Publications: 2 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-AS1 (HGNC:42440): (MYLK antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000299345: Loss of protein. Functional experiments described in manuscript.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-123664245-T-TCGCTTTC is Pathogenic according to our data. Variant chr3-123664245-T-TCGCTTTC is described in ClinVar as Pathogenic. ClinVar VariationId is 264987.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	NM_053025.4	MANE Select	c.3838_3844dupGAAAGCG	p.Glu1282GlyfsTer51	frameshift	Exon 23 of 34	NP_444253.3
	MYLK	NM_053027.4		c.3838_3844dupGAAAGCG	p.Glu1282GlyfsTer51	frameshift	Exon 23 of 33	NP_444255.3
	MYLK	NM_053026.4		c.3631_3637dupGAAAGCG	p.Glu1213GlyfsTer51	frameshift	Exon 22 of 33	NP_444254.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK	ENST00000360304.8	TSL:5 MANE Select	c.3838_3844dupGAAAGCG	p.Glu1282GlyfsTer51	frameshift	Exon 23 of 34	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000464489.5	TSL:1	n.*3417_*3423dupGAAAGCG		non_coding_transcript_exon	Exon 22 of 33	ENSP00000417798.1	F8WBL7
	MYLK	ENST00000464489.5	TSL:1	n.*3417_*3423dupGAAAGCG		3_prime_UTR	Exon 22 of 33	ENSP00000417798.1	F8WBL7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Megacystis, microcolon, hypoperistalsis syndrome (1)
1	-	-	Visceral myopathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553787823; hg19: chr3-123383092;