12-110914159-GACAC-GACACAC

Position:

• chr12-110914159-GACAC-GACACAC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000432.4(MYL2):​c.274+25_274+26dupGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0765 in 1,369,570 control chromosomes in the GnomAD database, including 1,729 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (549 hom., cov: 31)
  • Exomes 𝑓: 0.076 (1180 hom.)
• Consequence: MYL2 NM_000432.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.360

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 12-110914159-G-GAC is Benign according to our data. Variant chr12-110914159-G-GAC is described in ClinVar as [Likely_benign]. Clinvar id is 43462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL2	NM_000432.4	c.274+25_274+26dupGT		intron_variant		ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.232+25_232+26dupGT		intron_variant			NP_001393674.1
MYL2	NM_001406916.1	c.217+25_217+26dupGT		intron_variant			NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.274+25_274+26dupGT		intron_variant		1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.232+25_232+26dupGT		intron_variant		3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.217+25_217+26dupGT		intron_variant				ENSP00000499568.1
MYL2	ENST00000549029.1	n.105+25_105+26dupGT		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0776 AC: 11644 AN: 149990 Hom.: 550 Cov.: 31

Gnomad AFR AF: 0.0819

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.0682

Gnomad MID AF: 0.0649

Gnomad NFE AF: 0.0702

Gnomad OTH AF: 0.0533

GnomAD4 exome AF: 0.0764 AC: 93138 AN: 1219476 Hom.: 1180 Cov.: 16 AF XY: 0.0794 AC XY: 48757 AN XY: 613876

Gnomad4 AFR exome AF: 0.0809

Gnomad4 AMR exome AF: 0.0336

Gnomad4 ASJ exome AF: 0.0365

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.0721

Gnomad4 NFE exome AF: 0.0680

Gnomad4 OTH exome AF: 0.0712

GnomAD4 genome AF: 0.0776 AC: 11645 AN: 150094 Hom.: 549 Cov.: 31 AF XY: 0.0801 AC XY: 5859 AN XY: 73186

Gnomad4 AFR AF: 0.0820

Gnomad4 AMR AF: 0.0456

Gnomad4 ASJ AF: 0.0351

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.0682

Gnomad4 NFE AF: 0.0702

Gnomad4 OTH AF: 0.0522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 26, 2011	274+26_274+27insGT in intron 4 of MYL2: This variant is not expected to have cl inical or pathological significance because it does not alter an amino acid resi due and is not located in the highly conserved region of the 5' splice site. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 30, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142567411; hg19: chr12-111351963;