12-110913139-C-G

Variant names:

• chr12-110913139-C-G
• NM_000432.4:c.359G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000432.4(MYL2):​c.359G>C​(p.Arg120Pro) variant causes a missense change involving the alteration of a non-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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R120W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

Genes affected

MYL2 (HGNC:7583): (myosin light chain 2) This gene encodes a major sarcomeric protein in mammalian striated muscle. The encoded protein plays a role in embryonic heart muscle structure and function, while phosphorylation of the encoded protein is involved in cardiac myosin cycling kinetics, torsion and function in adults. Mutations in this gene are associated with hypertrophic cardiomyopathy 10 and infant-onset myopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (size 164) in uniprot entity MLRV_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-110913140-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.359G>C	p.Arg120Pro	missense_variant	Exon 6 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.317G>C	p.Arg106Pro	missense_variant	Exon 5 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.302G>C	p.Arg101Pro	missense_variant	Exon 6 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.359G>C	p.Arg120Pro	missense_variant	Exon 6 of 7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.317G>C	p.Arg106Pro	missense_variant	Exon 5 of 6	3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.302G>C	p.Arg101Pro	missense_variant	Exon 6 of 7			ENSP00000499568.1
MYL2	ENST00000549029.1	n.291G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 16, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYL2 c.359G>C (p.Arg120Pro) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.359G>C in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Uncertain	0.12
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Benign	0.099
Eigen_PC	Benign	-0.051
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.014	D;T
Polyphen		0.81	P;.
Vest4		0.59
MutPred		0.61		Gain of catalytic residue at K115 (P = 0.0022);.;
MVP		0.90
MPC		1.0
ClinPred		0.90	D
GERP RS		-0.34
Varity_R		0.69
gMVP		0.90

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-111350943;