rs1060499882

chr12-110919193-C-Achr12-110919193-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The NM_000432.4(MYL2):c.4G>T(p.Ala2Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MYL2
NM_000432.4 missense, splice_region

Scores

Splicing: ADA: 0.6754

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.0910

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 Likely_benign. Variant got -1 ACMG points.

PM1

In a chain Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (size 164) in uniprot entity MLRV_HUMAN there are 53 pathogenic changes around while only 9 benign (85%) in NM_000432.4

BP4

Computational evidence support a benign effect (MetaRNN=0.14463133).

BP6

Variant 12-110919193-C-A is Benign according to our data. Variant chr12-110919193-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 927922.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYL2	NM_000432.4 linkuse as main transcript	c.4G>T	p.Ala2Ser	missense_variant, splice_region_variant	2/7	ENST00000228841.15
MYL2	NM_001406745.1 linkuse as main transcript	c.4G>T	p.Ala2Ser	missense_variant, splice_region_variant	2/6
MYL2	NM_001406916.1 linkuse as main transcript	c.-54G>T		splice_region_variant, 5_prime_UTR_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MYL2	ENST00000228841.15 linkuse as main transcript	c.4G>T	p.Ala2Ser	missense_variant, splice_region_variant	2/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1 linkuse as main transcript	c.4G>T	p.Ala2Ser	missense_variant, splice_region_variant	2/6	3
MYL2	ENST00000546404.1 linkuse as main transcript	c.4G>T	p.Ala2Ser	missense_variant, splice_region_variant	2/2	2
MYL2	ENST00000663220.1 linkuse as main transcript	c.-54G>T		splice_region_variant, 5_prime_UTR_variant	2/7

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151954

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:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250904

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135616

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460640

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726584

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151954

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74198

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:

0.0000946

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 16, 2020

This sequence change replaces alanine with serine at codon 2 of the MYL2 protein (p.Ala2Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYL2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

CardioboostCm

Benign

0.0083

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.40

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.86

D;D

M_CAP

Benign

0.068

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.23

Sift

Benign

0.25

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0

B;.

Vest4

0.31

MutPred

0.25

Gain of phosphorylation at A2 (P = 0.0034);Gain of phosphorylation at A2 (P = 0.0034);

MVP

0.71

MPC

0.47

ClinPred

0.17

GERP RS

-1.4

Varity_R

0.096

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.68

dbscSNV1_RF

Benign

0.50

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

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