chr20-31821649-T-C

Variant names:

• chr20-31821649-T-C
• rs6058469
• NM_033118.4:c.684T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033118.4(MYLK2):​c.684T>C​(p.Ile228Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0731 in 1,613,856 control chromosomes in the GnomAD database, including 4,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (663 hom., cov: 33)
  • Exomes 𝑓: 0.072 (4147 hom.)
• Consequence: MYLK2 NM_033118.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0970
• Publications: 8 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.64).
• BP6: Variant 20-31821649-T-C is Benign according to our data. Variant chr20-31821649-T-C is described in ClinVar as Benign. ClinVar VariationId is 46528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.097 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK2	NM_033118.4	MANE Select	c.684T>C	p.Ile228Ile	synonymous	Exon 4 of 13	NP_149109.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK2	ENST00000375985.5	TSL:1 MANE Select	c.684T>C	p.Ile228Ile	synonymous	Exon 4 of 13	ENSP00000365152.4
	MYLK2	ENST00000375994.6	TSL:1	c.684T>C	p.Ile228Ile	synonymous	Exon 3 of 12	ENSP00000365162.2

Frequencies

GnomAD3 genomes AF: 0.0877 AC: 13327 AN: 152012 Hom.: 659 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0624

Gnomad ASJ AF: 0.0856

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.0268

Gnomad FIN AF: 0.0725

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0766

Gnomad OTH AF: 0.0957

GnomAD2 exomes AF: 0.0653 AC: 16412 AN: 251312 AF XY: 0.0636

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.0459

Gnomad ASJ exome AF: 0.0826

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0705

Gnomad NFE exome AF: 0.0785

Gnomad OTH exome AF: 0.0742

GnomAD4 exome AF: 0.0716 AC: 104602 AN: 1461726 Hom.: 4147 Cov.: 33 AF XY: 0.0702 AC XY: 51073 AN XY: 727148

African (AFR) AF: 0.140 AC: 4672 AN: 33480

American (AMR) AF: 0.0485 AC: 2168 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0860 AC: 2248 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0266 AC: 2296 AN: 86258

European-Finnish (FIN) AF: 0.0701 AC: 3733 AN: 53278

Middle Eastern (MID) AF: 0.136 AC: 786 AN: 5766

European-Non Finnish (NFE) AF: 0.0757 AC: 84143 AN: 1111992

Other (OTH) AF: 0.0754 AC: 4552 AN: 60392

GnomAD4 genome AF: 0.0878 AC: 13364 AN: 152130 Hom.: 663 Cov.: 33 AF XY: 0.0852 AC XY: 6338 AN XY: 74388

African (AFR) AF: 0.137 AC: 5692 AN: 41504

American (AMR) AF: 0.0622 AC: 952 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0856 AC: 297 AN: 3468

East Asian (EAS) AF: 0.000969 AC: 5 AN: 5158

South Asian (SAS) AF: 0.0272 AC: 131 AN: 4812

European-Finnish (FIN) AF: 0.0725 AC: 768 AN: 10590

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0767 AC: 5211 AN: 67980

Other (OTH) AF: 0.0952 AC: 201 AN: 2112

Alfa AF: 0.0818 Hom.: 426

Bravo AF: 0.0903

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.0881

EpiControl AF: 0.0847

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Hypertrophic cardiomyopathy 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		-0.097
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs6058469; hg19: chr20-30409452; COSMIC: COSV65659605;