12-110915749-G-C

Variant names:

• chr12-110915749-G-C
• NM_000432.4:c.135C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1 PM1 PM2 PP3

The NM_000432.4(MYL2):​c.135C>G​(p.Asp45Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,862 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd. Synonymous variant affecting the same amino acid position (i.e. D45D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.54

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 9 ACMG points.

• PS1: Transcript NM_000432.4 (MYL2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a domain EF-hand 1 (size 35) in uniprot entity MLRV_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.135C>G	p.Asp45Glu	missense_variant	Exon 3 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406916.1	c.78C>G	p.Asp26Glu	missense_variant	Exon 3 of 7		NP_001393845.1
MYL2	NM_001406745.1	c.94-1425C>G		intron_variant	Intron 2 of 5		NP_001393674.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.135C>G	p.Asp45Glu	missense_variant	Exon 3 of 7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000663220.1	c.78C>G	p.Asp26Glu	missense_variant	Exon 3 of 7			ENSP00000499568.1
MYL2	ENST00000548438.1	c.94-1425C>G		intron_variant	Intron 2 of 5	3		ENSP00000447154.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
CardioboostCm	Uncertain	0.17
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.034	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.029	D
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.72
MutPred		0.43		Gain of catalytic residue at L49 (P = 0.045);
MVP		0.86
MPC		0.94
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.72
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-111353553;