Genetic Variant MYL2:c.274+23_274+26delGTGT (chr12-110914159-GACAC-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000432.4(MYL2):c.274+23_274+26delGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000085 in 1,223,398 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

MYL2
NM_000432.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.360

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 10
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
congenital fiber-type disproportion myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4 link	c.274+23_274+26delGTGT	intron_variant	Intron 4 of 6	ENST00000228841.15	NP_000423.2	P10916Q6IB42
MYL2	NM_001406745.1 link	c.232+23_232+26delGTGT	intron_variant	Intron 3 of 5		NP_001393674.1
MYL2	NM_001406916.1 link	c.217+23_217+26delGTGT	intron_variant	Intron 4 of 6		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15 link	c.274+23_274+26delGTGT		intron_variant	Intron 4 of 6	1	NM_000432.4	ENSP00000228841.8		P10916

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000859

AC:

AN:

116462

AF XY:

0.0000160

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 FIN exome

AF:

0.0000972

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000850

AC:

104

AN:

1223398

Hom.:

AF XY:

0.0000682

AC XY:

AN XY:

615828

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000105

AC:

AN:

28452

American (AMR)

AF:

0.00

AC:

AN:

41418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23336

East Asian (EAS)

AF:

0.00

AC:

AN:

36594

South Asian (SAS)

AF:

0.0000128

AC:

AN:

77992

European-Finnish (FIN)

AF:

0.0000202

AC:

AN:

49432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5172

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

909406

Other (OTH)

AF:

0.0000969

AC:

AN:

51596

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.234

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.36

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over