12-110914159-GACACACACAC-GACACACACACAC

Variant names:

• chr12-110914159-G-GAC
• rs142567411
• NM_000432.4:c.274+25_274+26dupGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000432.4(MYL2):​c.274+25_274+26dupGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0765 in 1,369,570 control chromosomes in the GnomAD database, including 1,729 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (549 hom., cov: 31)
  • Exomes 𝑓: 0.076 (1180 hom.)
• Consequence: MYL2 NM_000432.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.360
• Publications: 2 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-110914159-G-GAC is Benign according to our data. Variant chr12-110914159-G-GAC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

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+25_274+26dupGT		intron	N/A	NP_000423.2	P10916
	MYL2	NM_001406745.1		c.232+25_232+26dupGT		intron	N/A	NP_001393674.1	G3V1V8
	MYL2	NM_001406916.1		c.217+25_217+26dupGT		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+27insGT		intron	N/A	ENSP00000228841.8	P10916
	MYL2	ENST00000713800.1		c.274+26_274+27insGT		intron	N/A	ENSP00000519106.1	P10916
	MYL2	ENST00000713803.1		c.274+26_274+27insGT		intron	N/A	ENSP00000519109.1	P10916

Frequencies

GnomAD3 genomes AF: 0.0776 AC: 11644 AN: 149990 Hom.: 550 Cov.: 31

Gnomad AFR AF: 0.0819

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.0682

Gnomad MID AF: 0.0649

Gnomad NFE AF: 0.0702

Gnomad OTH AF: 0.0533

GnomAD2 exomes AF: 0.178 AC: 20713 AN: 116462 AF XY: 0.186

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.0751

Gnomad ASJ exome AF: 0.0860

Gnomad EAS exome AF: 0.338

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.0764 AC: 93138 AN: 1219476 Hom.: 1180 Cov.: 16 AF XY: 0.0794 AC XY: 48757 AN XY: 613876

African (AFR) AF: 0.0809 AC: 2295 AN: 28370

American (AMR) AF: 0.0336 AC: 1393 AN: 41412

Ashkenazi Jewish (ASJ) AF: 0.0365 AC: 851 AN: 23334

East Asian (EAS) AF: 0.209 AC: 7626 AN: 36568

South Asian (SAS) AF: 0.152 AC: 11816 AN: 77864

European-Finnish (FIN) AF: 0.0721 AC: 3567 AN: 49480

Middle Eastern (MID) AF: 0.0564 AC: 292 AN: 5174

European-Non Finnish (NFE) AF: 0.0680 AC: 61632 AN: 905792

Other (OTH) AF: 0.0712 AC: 3666 AN: 51482

GnomAD4 genome AF: 0.0776 AC: 11645 AN: 150094 Hom.: 549 Cov.: 31 AF XY: 0.0801 AC XY: 5859 AN XY: 73186

African (AFR) AF: 0.0820 AC: 3359 AN: 40966

American (AMR) AF: 0.0456 AC: 685 AN: 15034

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 121 AN: 3444

East Asian (EAS) AF: 0.212 AC: 1091 AN: 5136

South Asian (SAS) AF: 0.164 AC: 775 AN: 4726

European-Finnish (FIN) AF: 0.0682 AC: 695 AN: 10186

Middle Eastern (MID) AF: 0.0664 AC: 19 AN: 286

European-Non Finnish (NFE) AF: 0.0702 AC: 4727 AN: 67336

Other (OTH) AF: 0.0522 AC: 108 AN: 2068

Alfa AF: 0.0343 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Cardiomyopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

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;