rs3746597

Variant names:

• chr20-31821514-C-T
• rs3746597
• NM_033118.4:c.549C>T

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_033118.4(MYLK2):​c.549C>T​(p.His183His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00057 in 1,614,056 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (6 hom.)
• Consequence: MYLK2 NM_033118.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.35
• Publications: 3 publications found

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]

MYLK2 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 20-31821514-C-T is Benign according to our data. Variant chr20-31821514-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000573 (838/1461680) while in subpopulation EAS AF = 0.0193 (765/39700). AF 95% confidence interval is 0.0181. There are 6 homozygotes in GnomAdExome4. There are 388 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 82 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033118.4. 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
	MYLK2	NM_033118.4	MANE Select	c.549C>T	p.His183His	synonymous	Exon 4 of 13	NP_149109.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK2	ENST00000375985.5	TSL:1 MANE Select	c.549C>T	p.His183His	synonymous	Exon 4 of 13	ENSP00000365152.4
	MYLK2	ENST00000375994.6	TSL:1	c.549C>T	p.His183His	synonymous	Exon 3 of 12	ENSP00000365162.2
	MYLK2	ENST00000965978.1		c.549C>T	p.His183His	synonymous	Exon 4 of 13	ENSP00000636037.1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152258 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0138

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00131 AC: 329 AN: 251068 AF XY: 0.00123

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0168

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000573 AC: 838 AN: 1461680 Hom.: 6 Cov.: 32 AF XY: 0.000534 AC XY: 388 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0193 AC: 765 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.000432 AC: 23 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112010

Other (OTH) AF: 0.000447 AC: 27 AN: 60392

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152376 Hom.: 1 Cov.: 33 AF XY: 0.000684 AC XY: 51 AN XY: 74512

African (AFR) AF: 0.0000240 AC: 1 AN: 41592

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000224 Hom.: 0

Bravo AF: 0.000672

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 1 (1)
-	-	1	MYLK2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.16
DANN	Benign	0.41
PhyloP100		-2.4
Mutation Taster		=100/0	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: rs3746597; hg19: chr20-30409317;