rs1555258369

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

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:1U:1

Conservation

PhyloP100: 4.91

Variant links:

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]

MYL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4 link	c.3G>A	p.Met1?	start_lost, splice_region_variant	Exon 1 of 7	ENST00000228841.15	NP_000423.2	P10916Q6IB42
MYL2	NM_001406745.1 link	c.3G>A	p.Met1?	start_lost, splice_region_variant	Exon 1 of 6		NP_001393674.1
MYL2	NM_001406916.1 link	c.-55+862G>A		intron_variant	Intron 1 of 6		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYL2	ENST00000228841.15 link	c.3G>A	p.Met1?	start_lost, splice_region_variant	Exon 1 of 7	1	NM_000432.4	ENSP00000228841.8	P10916
MYL2	ENST00000548438.1 link	c.3G>A	p.Met1?	start_lost, splice_region_variant	Exon 1 of 6	3		ENSP00000447154.1	G3V1V8
MYL2	ENST00000546404.1 link	c.3G>A	p.Met1?	start_lost, splice_region_variant	Exon 1 of 2	2		ENSP00000499645.1	A0A590UK07
MYL2	ENST00000663220.1 link	c.-55+862G>A		intron_variant	Intron 1 of 6			ENSP00000499568.1	A0A590UJU8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

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.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

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:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial isolated restrictive cardiomyopathy

Pathogenic:1

May 15, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change affects the initiator methionine of the MYL2 mRNA. The next in-frame methionine is located at codon 20. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30297972). ClinVar contains an entry for this variant (Variation ID: 444868). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Benign

-0.71

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over