rs17340492

Positions:

• chr20-31826700-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_033118.4(MYLK2):​c.1068C>T​(p.Val356=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,613,986 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (14 hom., cov: 31)
  • Exomes 𝑓: 0.015 (208 hom.)
• Consequence: MYLK2 NM_033118.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.45

Genes affected

MYLK2 (HGNC:16243): (myosin light chain kinase 2) This gene encodes a myosin light chain kinase, a calcium/calmodulin dependent enzyme, that is exclusively expressed in adult skeletal muscle. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 20-31826700-C-T is Benign according to our data. Variant chr20-31826700-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-31826700-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0115 (1756/152106) while in subpopulation NFE AF= 0.0166 (1130/67990). AF 95% confidence interval is 0.0158. There are 14 homozygotes in gnomad4. There are 872 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1756 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYLK2	NM_033118.4	c.1068C>T	p.Val356=	synonymous_variant	7/13	ENST00000375985.5	NP_149109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYLK2	ENST00000375985.5	c.1068C>T	p.Val356=	synonymous_variant	7/13	1	NM_033118.4	ENSP00000365152	P1
MYLK2	ENST00000375994.6	c.1068C>T	p.Val356=	synonymous_variant	6/12	1		ENSP00000365162	P1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1757 AN: 151988 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.00343

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0115 AC: 2879 AN: 251434 Hom.: 22 AF XY: 0.0115 AC XY: 1558 AN XY: 135896

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00717

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0164

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0153 AC: 22329 AN: 1461880 Hom.: 208 Cov.: 33 AF XY: 0.0149 AC XY: 10854 AN XY: 727240

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00767

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.0218

Gnomad4 NFE exome AF: 0.0175

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.0115 AC: 1756 AN: 152106 Hom.: 14 Cov.: 31 AF XY: 0.0117 AC XY: 872 AN XY: 74346

Gnomad4 AFR AF: 0.00342

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000625

Gnomad4 FIN AF: 0.0211

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0152 Hom.: 10

Bravo AF: 0.0104

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0173

EpiControl AF: 0.0188

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 17, 2022	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2011	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2014	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. -

Hypertrophic cardiomyopathy 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 22, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	8.5
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs17340492; hg19: chr20-30414503;