12-110914159-GACACACACAC-GACAC

Variant names:

• chr12-110914159-GACACAC-G
• rs142567411
• NM_000432.4:c.274+21_274+26delGTGTGT

Variant summary

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

The NM_000432.4(MYL2):​c.274+21_274+26delGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000326 in 1,226,710 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: 0.0000033 (0 hom.)
• Consequence: MYL2 NM_000432.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.609
• 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: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.274+21_274+26delGTGTGT		intron_variant	Intron 4 of 6	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.232+21_232+26delGTGTGT		intron_variant	Intron 3 of 5		NP_001393674.1
MYL2	NM_001406916.1	c.217+21_217+26delGTGTGT		intron_variant	Intron 4 of 6		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.274+21_274+26delGTGTGT		intron_variant	Intron 4 of 6	1	NM_000432.4	ENSP00000228841.8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000326 AC: 4 AN: 1226710 Hom.: 0 AF XY: 0.00000648 AC XY: 4 AN XY: 617382

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28506

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: 0.0000128 AC: 1 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: 0.00000329 AC: 3 AN: 912062

Other (OTH) AF: 0.00 AC: 0 AN: 51758

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.001284), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.61

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;