NM_001012418.5:c.451G>C

Variant names:

• chr6-2685390-C-G
• rs796052168
• NM_001012418.5:c.451G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001012418.5(MYLK4):​c.451G>C​(p.Glu151Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,409,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. E151K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYLK4 NM_001012418.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

Genes affected

MYLK4 (HGNC:27972): (myosin light chain kinase family member 4) Predicted to enable myosin light chain kinase activity. Predicted to be involved in protein phosphorylation. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYLK4	NM_001012418.5	c.451G>C	p.Glu151Gln	missense_variant	Exon 6 of 13	ENST00000274643.9	NP_001012418.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYLK4	ENST00000274643.9	c.451G>C	p.Glu151Gln	missense_variant	Exon 6 of 13	1	NM_001012418.5	ENSP00000274643.7
MYLK4	ENST00000698899.1	c.619G>C	p.Glu207Gln	missense_variant	Exon 6 of 13			ENSP00000514016.1
MYLK4	ENST00000647417.1	c.433G>C	p.Glu145Gln	missense_variant	Exon 5 of 12			ENSP00000494309.1
MYLK4	ENST00000698900.1	n.712G>C		non_coding_transcript_exon_variant	Exon 7 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1409284 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 700540

African (AFR) AF: 0.00 AC: 0 AN: 31914

American (AMR) AF: 0.00 AC: 0 AN: 43082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24152

East Asian (EAS) AF: 0.00 AC: 0 AN: 35794

South Asian (SAS) AF: 0.00 AC: 0 AN: 85758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077486

Other (OTH) AF: 0.00 AC: 0 AN: 56902

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.5	.;M
PhyloP100		7.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	.;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.0020	.;D
Polyphen		1.0	.;D
Vest4		0.93
MutPred		0.93		.;Gain of MoRF binding (P = 0.0628);
MVP		0.76
MPC		0.69
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.84
Mutation Taster		=19/81	disease causing

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: rs796052168; hg19: chr6-2685624;