rs28497577

Variant names:

• chr3-123793780-G-T
• rs28497577
• NM_053025.4:c.62C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-123793780-G-T
• chr3-123793780-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_053025.4(MYLK):​c.62C>A​(p.Pro21His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,613,450 control chromosomes in the GnomAD database, including 13,562 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P21S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.17 (3409 hom., cov: 32)
  • Exomes 𝑓: 0.10 (10153 hom.)
• Consequence: MYLK NM_053025.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.192
• Publications: 43 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
• megacystis-microcolon-intestinal hypoperistalsis syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: G2P
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005610466).
• BP6: Variant 3-123793780-G-T is Benign according to our data. Variant chr3-123793780-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

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.62C>A	p.Pro21His	missense	Exon 4 of 34	NP_444253.3
	MYLK	NM_053027.4		c.62C>A	p.Pro21His	missense	Exon 4 of 33	NP_444255.3
	MYLK	NM_053026.4		c.62C>A	p.Pro21His	missense	Exon 4 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.62C>A	p.Pro21His	missense	Exon 4 of 34	ENSP00000353452.3	Q15746-1
	MYLK	ENST00000464489.5	TSL:1	n.62C>A		non_coding_transcript_exon	Exon 4 of 33	ENSP00000417798.1	F8WBL7
	MYLK	ENST00000687848.1		c.92C>A	p.Pro31His	missense	Exon 2 of 32	ENSP00000508761.1	A0A8I5KU53

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25753 AN: 151480 Hom.: 3395 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.0667

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.0430

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0874

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.118 AC: 29719 AN: 251342 AF XY: 0.119

Gnomad AFR exome AF: 0.376

Gnomad AMR exome AF: 0.0704

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.0661

Gnomad FIN exome AF: 0.0502

Gnomad NFE exome AF: 0.0894

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.103 AC: 150124 AN: 1461852 Hom.: 10153 Cov.: 32 AF XY: 0.105 AC XY: 76213 AN XY: 727224

African (AFR) AF: 0.389 AC: 13038 AN: 33480

American (AMR) AF: 0.0745 AC: 3331 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4704 AN: 26134

East Asian (EAS) AF: 0.0677 AC: 2689 AN: 39698

South Asian (SAS) AF: 0.201 AC: 17379 AN: 86254

European-Finnish (FIN) AF: 0.0527 AC: 2814 AN: 53418

Middle Eastern (MID) AF: 0.137 AC: 788 AN: 5768

European-Non Finnish (NFE) AF: 0.0879 AC: 97770 AN: 1111984

Other (OTH) AF: 0.126 AC: 7611 AN: 60392

GnomAD4 genome AF: 0.170 AC: 25818 AN: 151598 Hom.: 3409 Cov.: 32 AF XY: 0.167 AC XY: 12410 AN XY: 74122

African (AFR) AF: 0.375 AC: 15483 AN: 41322

American (AMR) AF: 0.100 AC: 1528 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 579 AN: 3454

East Asian (EAS) AF: 0.0662 AC: 339 AN: 5118

South Asian (SAS) AF: 0.210 AC: 1007 AN: 4794

European-Finnish (FIN) AF: 0.0430 AC: 455 AN: 10582

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0874 AC: 5923 AN: 67794

Other (OTH) AF: 0.162 AC: 340 AN: 2096

Alfa AF: 0.114 Hom.: 5153

Bravo AF: 0.181

TwinsUK AF: 0.0860 AC: 319

ALSPAC AF: 0.0843 AC: 325

ESP6500AA AF: 0.363 AC: 1598

ESP6500EA AF: 0.0938 AC: 807

ExAC AF: 0.126 AC: 15333

Asia WGS AF: 0.212 AC: 739 AN: 3478

EpiCase AF: 0.0953

EpiControl AF: 0.0920

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Aortic aneurysm, familial thoracic 7 (2)
-	-	2	not provided (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.9
DANN	Benign	0.79
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.26	N
PhyloP100		-0.19
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.12
Sift	Benign	0.47	T
Sift4G	Benign	0.28	T
Polyphen		0.0020	B
Vest4		0.11
MPC		0.70
ClinPred		0.011	T
GERP RS		0.15
PromoterAI		-0.019	Neutral
Varity_R		0.076
gMVP		0.27
Mutation Taster		=100/0	polymorphism (auto)

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: rs28497577; hg19: chr3-123512627; COSMIC: COSV60607769;