rs2301610

chr12-110915752-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000432.4(MYL2):c.132T>C(p.Ile44=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0921 in 1,613,832 control chromosomes in the GnomAD database, including 7,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (651 hom., cov: 32)
  • Exomes 𝑓: 0.093 (7101 hom.)
• Consequence: MYL2 NM_000432.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: -1.09

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 12-110915752-A-G is Benign according to our data. Variant chr12-110915752-A-G is described in ClinVar as [Benign]. Clinvar id is 31771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110915752-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL2	NM_000432.4	c.132T>C	p.Ile44=	synonymous_variant	3/7	ENST00000228841.15
MYL2	NM_001406916.1	c.75T>C	p.Ile25=	synonymous_variant	3/7
MYL2	NM_001406745.1	c.94-1428T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.132T>C	p.Ile44=	synonymous_variant	3/7	1	NM_000432.4	P1
MYL2	ENST00000663220.1	c.75T>C	p.Ile25=	synonymous_variant	3/7
MYL2	ENST00000548438.1	c.94-1428T>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0854 AC: 12992 AN: 152060 Hom.: 651 Cov.: 32

Gnomad AFR AF: 0.0708

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.0549

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0850

Gnomad OTH AF: 0.0575

GnomAD3 exomes AF: 0.101 AC: 25295 AN: 251412 Hom.: 1630 AF XY: 0.105 AC XY: 14263 AN XY: 135872

Gnomad AFR exome AF: 0.0696

Gnomad AMR exome AF: 0.0386

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.237

Gnomad SAS exome AF: 0.168

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0871

Gnomad OTH exome AF: 0.0870

GnomAD4 exome AF: 0.0928 AC: 135614 AN: 1461654 Hom.: 7101 Cov.: 32 AF XY: 0.0953 AC XY: 69306 AN XY: 727150

Gnomad4 AFR exome AF: 0.0712

Gnomad4 AMR exome AF: 0.0389

Gnomad4 ASJ exome AF: 0.0369

Gnomad4 EAS exome AF: 0.221

Gnomad4 SAS exome AF: 0.166

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0864

Gnomad4 OTH exome AF: 0.0832

GnomAD4 genome AF: 0.0854 AC: 12995 AN: 152178 Hom.: 651 Cov.: 32 AF XY: 0.0894 AC XY: 6652 AN XY: 74398

Gnomad4 AFR AF: 0.0709

Gnomad4 AMR AF: 0.0547

Gnomad4 ASJ AF: 0.0363

Gnomad4 EAS AF: 0.211

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.0850

Gnomad4 OTH AF: 0.0564

Alfa AF: 0.0798 Hom.: 743

Bravo AF: 0.0778

Asia WGS AF: 0.125 AC: 432 AN: 3478

EpiCase AF: 0.0791

EpiControl AF: 0.0784

ClinVar

Significance: Benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2008	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hypertrophic cardiomyopathy 10 Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Benign:1 Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYL2)	Mar 26, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 16, 2018

- -

Congestive heart failure Benign:1

Benign, criteria provided, single submitter

clinical testing

Cohesion Phenomics

Oct 10, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	3.0
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2301610; hg19: chr12-111353556; COSMIC: COSV57406027; COSMIC: COSV57406027;