12-110912851-A-G

Variant names:

• chr12-110912851-A-G
• rs3782889
• NM_000432.4:c.402+245T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000432.4(MYL2):​c.402+245T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0726 in 152,116 control chromosomes in the GnomAD database, including 497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.073 (497 hom., cov: 33)
• Consequence: MYL2 NM_000432.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.582
• Publications: 36 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 12-110912851-A-G is Benign according to our data. Variant chr12-110912851-A-G is described in ClinVar as Benign. ClinVar VariationId is 1259772.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4	c.402+245T>C		intron_variant	Intron 6 of 6	ENST00000228841.15	NP_000423.2
MYL2	NM_001406745.1	c.360+245T>C		intron_variant	Intron 5 of 5		NP_001393674.1
MYL2	NM_001406916.1	c.345+245T>C		intron_variant	Intron 6 of 6		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL2	ENST00000228841.15	c.402+245T>C		intron_variant	Intron 6 of 6	1	NM_000432.4	ENSP00000228841.8

Frequencies

GnomAD3 genomes AF: 0.0727 AC: 11048 AN: 151998 Hom.: 498 Cov.: 33

Gnomad AFR AF: 0.0688

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0452

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0667

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0696

Gnomad OTH AF: 0.0484

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

GnomAD4 genome AF: 0.0726 AC: 11049 AN: 152116 Hom.: 497 Cov.: 33 AF XY: 0.0750 AC XY: 5577 AN XY: 74374

African (AFR) AF: 0.0689 AC: 2861 AN: 41502

American (AMR) AF: 0.0451 AC: 689 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3464

East Asian (EAS) AF: 0.212 AC: 1096 AN: 5174

South Asian (SAS) AF: 0.137 AC: 662 AN: 4826

European-Finnish (FIN) AF: 0.0667 AC: 706 AN: 10592

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0696 AC: 4731 AN: 67966

Other (OTH) AF: 0.0474 AC: 100 AN: 2110

Alfa AF: 0.0676 Hom.: 949

Bravo AF: 0.0686

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.2
DANN	Benign	0.76
PhyloP100		-0.58
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: rs3782889; hg19: chr12-111350655;