12-110911149-G-C

Variant names:

• chr12-110911149-G-C
• rs374328118
• NM_000432.4:c.429C>G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000432.4(MYL2):​c.429C>G​(p.Pro143Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYL2 NM_000432.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00800

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-110911149-G-C is Benign according to our data. Variant chr12-110911149-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 43476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.008 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.429C>G	p.Pro143Pro	synonymous_variant	Exon 7 of 7	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.387C>G	p.Pro129Pro	synonymous_variant	Exon 6 of 6		NP_001393674.1
MYL2	NM_001406916.1	c.372C>G	p.Pro124Pro	synonymous_variant	Exon 7 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.429C>G	p.Pro143Pro	synonymous_variant	Exon 7 of 7	1	NM_000432.4	ENSP00000228841.8
MYL2	ENST00000548438.1	c.387C>G	p.Pro129Pro	synonymous_variant	Exon 6 of 6	3		ENSP00000447154.1
MYL2	ENST00000663220.1	c.372C>G	p.Pro124Pro	synonymous_variant	Exon 7 of 7			ENSP00000499568.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 248952 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134738

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461712 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 17, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro143Pro in exon 7 of MYL2: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. This variant has been identified in 0.03% (1/37 38) of African American chromosomes from a broad population by the NHLBI Exome S equencing Project (http://evs.gs.washington.edu/EVS/) Pro143Pro in exon 7 of M YL2 (allele frequency = 0.03%, 1/3738) ** -

Jan 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYL2-related disorder Benign:1

May 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypertrophic cardiomyopathy 10 Benign:1

Oct 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Aug 15, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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	-0.58
CADD	Benign	5.1
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs374328118; hg19: chr12-111348953;