rs56056823

Variant names:

• chr3-123640360-C-T
• rs56056823
• NM_053025.4:c.4764G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_053025.4(MYLK):​c.4764G>A​(p.Pro1588Pro) 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:17
• Conservation: PhyloP100: -1.09
• Publications: 4 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 196142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

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.4764G>A	p.Pro1588Pro	synonymous	Exon 28 of 34	NP_444253.3
	MYLK	NM_053027.4		c.4764G>A	p.Pro1588Pro	synonymous	Exon 28 of 33	NP_444255.3
	MYLK	NM_053026.4		c.4557G>A	p.Pro1519Pro	synonymous	Exon 27 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.4764G>A	p.Pro1588Pro	synonymous	Exon 28 of 34	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000464489.5	TSL:1	n.*4343G>A		non_coding_transcript_exon	Exon 27 of 33	ENSP00000417798.1	F8WBL7
	MYLK	ENST00000464489.5	TSL:1	n.*4343G>A		3_prime_UTR	Exon 27 of 33	ENSP00000417798.1	F8WBL7

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

GnomAD2 exomes AF: 0.00448 AC: 1126 AN: 251474 AF XY: 0.00433

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 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

African (AFR) AF: 0.00119 AC: 40 AN: 33480

American (AMR) AF: 0.00286 AC: 128 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00337 AC: 88 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86258

European-Finnish (FIN) AF: 0.00195 AC: 104 AN: 53418

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00895 AC: 9949 AN: 1112008

Other (OTH) AF: 0.00644 AC: 389 AN: 60396

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

African (AFR) AF: 0.00118 AC: 49 AN: 41476

American (AMR) AF: 0.00406 AC: 62 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000835 AC: 4 AN: 4788

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00844 AC: 574 AN: 67996

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00626 Hom.: 5

Bravo AF: 0.00487

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00774

EpiControl AF: 0.00705

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	2	Aortic aneurysm, familial thoracic 7 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	Aortic aneurysm, familial thoracic 7;C5542316:Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.2
DANN	Benign	0.83
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	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

Other links and lift over

dbSNP: rs56056823; hg19: chr3-123359207;