chr12-110911160-C-A

Variant names:

• chr12-110911160-C-A
• NM_000432.4:c.418G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000432.4(MYL2):​c.418G>T​(p.Ala140Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.367

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 Uncertain_significance. Variant got 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.09272009).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.418G>T	p.Ala140Ser	missense_variant	Exon 7 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.376G>T	p.Ala126Ser	missense_variant	Exon 6 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.361G>T	p.Ala121Ser	missense_variant	Exon 7 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.418G>T	p.Ala140Ser	missense_variant	Exon 7 of 7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.376G>T	p.Ala126Ser	missense_variant	Exon 6 of 6	3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.361G>T	p.Ala121Ser	missense_variant	Exon 7 of 7			ENSP00000499568.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461178 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726866

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
CardioboostCm	Benign	0.00099
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.093	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.080
Sift	Benign	0.59	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.0010	B;.
Vest4		0.069
MutPred		0.39		Gain of catalytic residue at A141 (P = 0.0015);.;
MVP		0.75
MPC		0.39
ClinPred		0.074	T
GERP RS		1.9
Varity_R		0.060
gMVP		0.39

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-111348964;