12-110920527-C-T

Position:

• chr12-110920527-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000432.4(MYL2):​c.3G>A​(p.Met1?) variant causes a start lost, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MYL2 NM_000432.4 start_lost, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.91

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-110920527-C-T is Pathogenic according to our data. Variant chr12-110920527-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 444868.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL2	NM_000432.4	c.3G>A	p.Met1?	start_lost, splice_region_variant	1/7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.3G>A	p.Met1?	start_lost, splice_region_variant	1/6		NP_001393674.1
MYL2	NM_001406916.1	c.-55+862G>A		intron_variant			NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.3G>A	p.Met1?	start_lost, splice_region_variant	1/7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.3G>A	p.Met1?	start_lost, splice_region_variant	1/6	3		ENSP00000447154.1
MYL2	ENST00000546404.1	c.3G>A	p.Met1?	start_lost, splice_region_variant	1/2	2		ENSP00000499645.1
MYL2	ENST00000663220.1	c.-55+862G>A		intron_variant				ENSP00000499568.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial isolated restrictive cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre

May 15, 2017

The patient presented with typical signs of restrictive cardiomyopathy at 24 y.o. No signs of system disorder haven been noted. The family history did not report a consanguinity with homozygous status of the mutation suspect with condition. -

Hypertrophic cardiomyopathy 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 444868). Disruption of the initiator codon has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30297972). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the MYL2 mRNA. The next in-frame methionine is located at codon 20. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.71	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.0060	B;.
Vest4		0.87
MutPred		0.63		Gain of catalytic residue at P3 (P = 5e-04);Gain of catalytic residue at P3 (P = 5e-04);
MVP		0.90
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.82
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.040		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: rs1555258369; hg19: chr12-111358331;