12-110911082-C-A

Position:

• chr12-110911082-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000432.4(MYL2):​c.496G>T​(p.Asp166Tyr) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D166N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.21

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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 chr12-110911081-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31769.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• PP5: Variant 12-110911082-C-A is Pathogenic according to our data. Variant chr12-110911082-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181436.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL2	NM_000432.4	c.496G>T	p.Asp166Tyr	missense_variant	7/7	ENST00000228841.15
MYL2	NM_001406745.1	c.454G>T	p.Asp152Tyr	missense_variant	6/6
MYL2	NM_001406916.1	c.439G>T	p.Asp147Tyr	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.496G>T	p.Asp166Tyr	missense_variant	7/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.454G>T	p.Asp152Tyr	missense_variant	6/6	3
MYL2	ENST00000663220.1	c.439G>T	p.Asp147Tyr	missense_variant	7/7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 29, 2015

p.Asp166Tyr (GAC>TAC): c.496 G>T in exon 7 of the MYL2 gene (NM_000432.3); While the D166Y mutation in the MYL2 gene has not been reported to our knowledge, a mutation affecting this same residue, (D166V) has been reported in one individual with HCM, was absent in 200 control chromosomes and co-segregated with disease (Richard et al., 2003). Additionally, functional studies have shown that D166V alters myosin cross-bridge kinetics, increases calcium sensitivity, decreases maximal contractile force development and slows rates of force relaxation in myocardium (Kerrick et al., 2009; Wang et al., 2013). Furthermore, a mutation in a nearby residue (G162R) has been reported in association with HCM, further supporting the functional importance of this residue and this region of the protein. D166Y results in a non-conservative amino acid substitution at a position that is conserved among vertebrates. In silico analysis predicts D166Y is damaging to the protein structure/function. D166Y was also not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, D166Y in the MYL2 gene is interpreted as a likely disease-causing mutation. The variant is found in HCM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
CardioboostCm	Uncertain	0.64
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.77
MutPred		0.47		Gain of catalytic residue at E163 (P = 0.047);.;
MVP		0.95
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs730880952; hg19: chr12-111348886;