2-210293791-A-C

Position:

• chr2-210293791-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_079420.3(MYL1):​c.488T>G​(p.Met163Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYL1 NM_079420.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.32

Genes affected

MYL1 (HGNC:7582): (myosin light chain 1) Myosin is a hexameric ATPase cellular motor protein. It is composed of two heavy chains, two nonphosphorylatable alkali light chains, and two phosphorylatable regulatory light chains. This gene encodes a myosin alkali light chain expressed in fast skeletal muscle. Two transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

MYL1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL1	NM_079420.3	c.488T>G	p.Met163Arg	missense_variant	5/7	ENST00000352451.4	NP_524144.1
MYL1	NM_079422.3	c.356T>G	p.Met119Arg	missense_variant	5/7		NP_524146.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL1	ENST00000352451.4	c.488T>G	p.Met163Arg	missense_variant	5/7	1	NM_079420.3	ENSP00000307280.4
MYL1	ENST00000341685.8	c.356T>G	p.Met119Arg	missense_variant	5/7	1		ENSP00000343321.4
MYL1	ENST00000484290.1	n.619T>G		non_coding_transcript_exon_variant	6/6	5
MYL1	ENST00000496436.5	n.591T>G		non_coding_transcript_exon_variant	5/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myopathy with reduced type 2 muscle fibers Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Dec 04, 2024	This variant is interpreted as a variant of uncertain significance for Myopathy, congenital, with fast-twitch type II fiber atrophy, autosomal recessive. This missense change is absent from large population cohorts (gnomAD v4.1.0; PM2_supporting); computational evidence support a damaging effect on gene or gene product (REVEL 0.868; PP3_moderate ); experimental evidence suggest that the variant affects protein function (PMID: 30215711; PS3_supporting). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 16, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.9	.;H
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.97	D;D
Vest4		0.92
MutPred		0.54		.;Gain of methylation at K162 (P = 0.0264);
MVP		0.93
MPC		0.53
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1259220084; hg19: chr2-211158515;