rs12301951

Positions:

• chr12-110919207-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000432.4(MYL2):​c.4-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00722 in 1,610,280 control chromosomes in the GnomAD database, including 704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (367 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (337 hom.)
• Consequence: MYL2 NM_000432.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.820

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-110919207-G-A is Benign according to our data. Variant chr12-110919207-G-A is described in ClinVar as [Benign]. Clinvar id is 43474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110919207-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL2	NM_000432.4	c.4-14C>T		intron_variant		ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.4-14C>T		intron_variant			NP_001393674.1
MYL2	NM_001406916.1	c.-54-14C>T		intron_variant			NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.4-14C>T		intron_variant		1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.4-14C>T		intron_variant		3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.-54-14C>T		intron_variant				ENSP00000499568.1
MYL2	ENST00000546404.1	c.4-14C>T		intron_variant		2		ENSP00000499645.1

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 5812 AN: 151830 Hom.: 364 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0221

GnomAD3 exomes AF: 0.00999 AC: 2495 AN: 249696 Hom.: 135 AF XY: 0.00734 AC XY: 991 AN XY: 134994

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.00744

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000416

Gnomad OTH exome AF: 0.00426

GnomAD4 exome AF: 0.00397 AC: 5794 AN: 1458332 Hom.: 337 Cov.: 30 AF XY: 0.00344 AC XY: 2497 AN XY: 725512

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.00813

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000182

Gnomad4 OTH exome AF: 0.00895

GnomAD4 genome AF: 0.0384 AC: 5834 AN: 151948 Hom.: 367 Cov.: 32 AF XY: 0.0371 AC XY: 2756 AN XY: 74280

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.0134

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.00657 Hom.: 12

Bravo AF: 0.0450

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 23, 2011	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 10 Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 02, 2018

- -

Congestive heart failure Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Oct 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.70

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

LitVar

Other links and lift over

dbSNP: rs12301951; hg19: chr12-111357011;