12-110914159-GACACACACAC-GACACACACACACACACAC

Variant names:

• chr12-110914159-G-GACACACAC
• rs142567411
• NM_000432.4:c.274+19_274+26dupGTGTGTGT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000432.4(MYL2):​c.274+19_274+26dupGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000163 in 1,226,752 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: MYL2 NM_000432.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.360
• 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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.274+19_274+26dupGTGTGTGT		intron	N/A	NP_000423.2	P10916
	MYL2	NM_001406745.1		c.232+19_232+26dupGTGTGTGT		intron	N/A	NP_001393674.1	G3V1V8
	MYL2	NM_001406916.1		c.217+19_217+26dupGTGTGTGT		intron	N/A	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.274+26_274+27insGTGTGTGT		intron	N/A	ENSP00000228841.8	P10916
	MYL2	ENST00000713800.1		c.274+26_274+27insGTGTGTGT		intron	N/A	ENSP00000519106.1	P10916
	MYL2	ENST00000713803.1		c.274+26_274+27insGTGTGTGT		intron	N/A	ENSP00000519109.1	P10916

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000163 AC: 2 AN: 1226752 Hom.: 0 Cov.: 16 AF XY: 0.00000162 AC XY: 1 AN XY: 617398

African (AFR) AF: 0.00 AC: 0 AN: 28508

American (AMR) AF: 0.00 AC: 0 AN: 41470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23398

East Asian (EAS) AF: 0.00 AC: 0 AN: 36672

South Asian (SAS) AF: 0.00 AC: 0 AN: 78066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5180

European-Non Finnish (NFE) AF: 0.00000219 AC: 2 AN: 912100

Other (OTH) AF: 0.00 AC: 0 AN: 51760

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36

Splicing

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

Other links and lift over

dbSNP: rs142567411; hg19: chr12-111351963;