12-110915044-A-C

Variant names:

• chr12-110915044-A-C
• rs933296
• NM_000432.4:c.169+671T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000432.4(MYL2):​c.169+671T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.743 in 152,162 control chromosomes in the GnomAD database, including 42,897 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (42897 hom., cov: 32)
• Consequence: MYL2 NM_000432.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.37
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.169+671T>G		intron_variant	Intron 3 of 6	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.94-720T>G		intron_variant	Intron 2 of 5		NP_001393674.1
MYL2	NM_001406916.1	c.112+671T>G		intron_variant	Intron 3 of 6		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.169+671T>G		intron_variant	Intron 3 of 6	1	NM_000432.4	ENSP00000228841.8

Frequencies

GnomAD3 genomes AF: 0.743 AC: 113006 AN: 152044 Hom.: 42846 Cov.: 32

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.745

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.679

Gnomad OTH AF: 0.708

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.743 AC: 113126 AN: 152162 Hom.: 42897 Cov.: 32 AF XY: 0.742 AC XY: 55197 AN XY: 74368

African (AFR) AF: 0.893 AC: 37099 AN: 41526

American (AMR) AF: 0.745 AC: 11389 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1909 AN: 3466

East Asian (EAS) AF: 0.680 AC: 3522 AN: 5176

South Asian (SAS) AF: 0.719 AC: 3468 AN: 4822

European-Finnish (FIN) AF: 0.677 AC: 7156 AN: 10568

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.679 AC: 46174 AN: 68008

Other (OTH) AF: 0.705 AC: 1487 AN: 2108

Alfa AF: 0.690 Hom.: 72643

Bravo AF: 0.752

Asia WGS AF: 0.695 AC: 2415 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.21
DANN	Benign	0.71
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs933296; hg19: chr12-111352848;