NM_000432.4:c.444C>T

Variant names:

• chr12-110911134-G-A
• rs1555257596
• NM_000432.4:c.444C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_000432.4(MYL2):​c.444C>T​(p.Gly148Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene MYL2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYL2 NM_000432.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.682
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), G2P
• 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

ACMG classification

Specifications for MYL2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-110911134-G-A is Benign according to our data. Variant chr12-110911134-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 464146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.682 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000432.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL2	NM_000432.4	MANE Select	c.444C>T	p.Gly148Gly	synonymous	Exon 7 of 7	NP_000423.2	P10916
	MYL2	NM_001406745.1		c.402C>T	p.Gly134Gly	synonymous	Exon 6 of 6	NP_001393674.1	G3V1V8
	MYL2	NM_001406916.1		c.387C>T	p.Gly129Gly	synonymous	Exon 7 of 7	NP_001393845.1	A0A590UJU8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL2	ENST00000228841.15	TSL:1 MANE Select	c.444C>T	p.Gly148Gly	synonymous	Exon 7 of 7	ENSP00000228841.8	P10916
	MYL2	ENST00000713800.1		c.444C>T	p.Gly148Gly	synonymous	Exon 8 of 8	ENSP00000519106.1	P10916
	MYL2	ENST00000713803.1		c.444C>T	p.Gly148Gly	synonymous	Exon 8 of 8	ENSP00000519109.1	P10916

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		0.68

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

Other links and lift over

dbSNP: rs1555257596; hg19: chr12-111348938;