chr20-31823495-C-G

Variant names:

• chr20-31823495-C-G
• rs142620954
• NM_033118.4:c.791C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033118.4(MYLK2):​c.791C>G​(p.Pro264Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,982 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P264L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYLK2 NM_033118.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.99
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK2	NM_033118.4	c.791C>G	p.Pro264Arg	missense_variant	Exon 5 of 13	ENST00000375985.5	NP_149109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK2	ENST00000375985.5	c.791C>G	p.Pro264Arg	missense_variant	Exon 5 of 13	1	NM_033118.4	ENSP00000365152.4
MYLK2	ENST00000375994.6	c.791C>G	p.Pro264Arg	missense_variant	Exon 4 of 12	1		ENSP00000365162.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460982 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726800

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52552

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		3.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.94	P;P
Vest4		0.47
MutPred		0.29		Loss of glycosylation at P264 (P = 0.0085);Loss of glycosylation at P264 (P = 0.0085);
MVP		0.85
MPC		0.27
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.46
gMVP		0.50
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs142620954; hg19: chr20-30411298;