20-31819588-C-T

Variant names:

• chr20-31819588-C-T
• rs2062241187
• NM_033118.4:c.8C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_033118.4(MYLK2):​c.8C>T​(p.Thr3Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000429 in 1,399,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: MYLK2 NM_033118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24658224).
• BS2: High AC in GnomAdExome4 at 6 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK2	NM_033118.4	c.8C>T	p.Thr3Ile	missense_variant	Exon 2 of 13	ENST00000375985.5	NP_149109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK2	ENST00000375985.5	c.8C>T	p.Thr3Ile	missense_variant	Exon 2 of 13	1	NM_033118.4	ENSP00000365152.4
MYLK2	ENST00000375994.6	c.8C>T	p.Thr3Ile	missense_variant	Exon 1 of 12	1		ENSP00000365162.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000429 AC: 6 AN: 1399276 Hom.: 0 Cov.: 31 AF XY: 0.00000435 AC XY: 3 AN XY: 690134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T3I variant (also known as c.8C>T), located in coding exon 1 of the MYLK2 gene, results from a C to T substitution at nucleotide position 8. The threonine at codon 3 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.0063	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.67	.;T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.067	T;T
Polyphen		0.74	P;P
Vest4		0.24
MutPred		0.19		Loss of glycosylation at T3 (P = 0.0499);Loss of glycosylation at T3 (P = 0.0499);
MVP		0.77
MPC		0.27
ClinPred		0.92	D
GERP RS		3.5
Varity_R		0.13
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2062241187; hg19: chr20-30407391;