NM_033118.4:c.1068C>T

Variant names:

• chr20-31826700-C-T
• rs17340492
• NM_033118.4:c.1068C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_033118.4(MYLK2):​c.1068C>T​(p.Val356Val) 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
• 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 -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 Benign/Likely_benign. ClinVar VariationId is 46517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1756 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYLK2	NM_033118.4	MANE Select	c.1068C>T	p.Val356Val	synonymous	Exon 7 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.1068C>T	p.Val356Val	synonymous	Exon 7 of 13	ENSP00000365152.4
	MYLK2	ENST00000375994.6	TSL:1	c.1068C>T	p.Val356Val	synonymous	Exon 6 of 12	ENSP00000365162.2
	MYLK2	ENST00000965978.1		c.1008C>T	p.Val336Val	synonymous	Exon 7 of 13	ENSP00000636037.1

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

GnomAD2 exomes AF: 0.0115 AC: 2879 AN: 251434 AF XY: 0.0115

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 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

African (AFR) AF: 0.00239 AC: 80 AN: 33480

American (AMR) AF: 0.00767 AC: 343 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 354 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86258

European-Finnish (FIN) AF: 0.0218 AC: 1165 AN: 53412

Middle Eastern (MID) AF: 0.00832 AC: 48 AN: 5768

European-Non Finnish (NFE) AF: 0.0175 AC: 19513 AN: 1112006

Other (OTH) AF: 0.0131 AC: 790 AN: 60396

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

African (AFR) AF: 0.00342 AC: 142 AN: 41482

American (AMR) AF: 0.0103 AC: 157 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000625 AC: 3 AN: 4800

European-Finnish (FIN) AF: 0.0211 AC: 223 AN: 10588

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0166 AC: 1130 AN: 67990

Other (OTH) AF: 0.0133 AC: 28 AN: 2108

Alfa AF: 0.0134 Hom.: 16

Bravo AF: 0.0104

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0173

EpiControl AF: 0.0188

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Hypertrophic cardiomyopathy 1 (2)
-	-	1	Cardiomyopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	8.5
DANN	Benign	0.85
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs17340492; hg19: chr20-30414503;