rs104894363

Variant names:

• chr12-110919160-C-T
• rs104894363
• NM_000432.4:c.37G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP4_Strong BP6

The NM_000432.4(MYL2):​c.37G>A​(p.Ala13Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000222 in 1,613,650 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYL2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 B:7 O:1
• Conservation: PhyloP100: 5.79
• Publications: 33 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

Specifications for MYL2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 34 uncertain in NM_000432.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.39564 (below the threshold of 3.09). Trascript score misZ: 1.1124 (below the threshold of 3.09). GenCC associations: The gene is linked to arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, dilated cardiomyopathy, myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, hypertrophic cardiomyopathy 10, congenital fiber-type disproportion myopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.020629168).
• BP6: Variant 12-110919160-C-T is Benign according to our data. Variant chr12-110919160-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14064.

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.37G>A	p.Ala13Thr	missense	Exon 2 of 7	NP_000423.2	P10916
	MYL2	NM_001406745.1		c.37G>A	p.Ala13Thr	missense	Exon 2 of 6	NP_001393674.1	G3V1V8
	MYL2	NM_001406916.1		c.-21G>A		5_prime_UTR	Exon 2 of 7	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.37G>A	p.Ala13Thr	missense	Exon 2 of 7	ENSP00000228841.8	P10916
	MYL2	ENST00000713800.1		c.37G>A	p.Ala13Thr	missense	Exon 3 of 8	ENSP00000519106.1	P10916
	MYL2	ENST00000713803.1		c.37G>A	p.Ala13Thr	missense	Exon 3 of 8	ENSP00000519109.1	P10916

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000366 AC: 92 AN: 251380 AF XY: 0.000397

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000224 AC: 327 AN: 1461462 Hom.: 1 Cov.: 30 AF XY: 0.000232 AC XY: 169 AN XY: 726976

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00498 AC: 130 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5462

European-Non Finnish (NFE) AF: 0.000152 AC: 169 AN: 1111988

Other (OTH) AF: 0.000364 AC: 22 AN: 60360

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74422

African (AFR) AF: 0.0000722 AC: 3 AN: 41524

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67988

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000368 Hom.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	4	1	Hypertrophic cardiomyopathy 10 (7)
-	3	2	not provided (5)
-	1	1	Cardiomyopathy (2)
-	1	1	Cardiovascular phenotype (2)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 1 (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
CardioboostCm	Uncertain	0.43
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.089
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.83	L
PhyloP100		5.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.53
Sift	Benign	0.066	T
Sift4G	Benign	0.17	T
Polyphen		0.80	P
Vest4		0.45
MVP		0.89
MPC		0.38
ClinPred		0.083	T
GERP RS		3.2
Varity_R		0.22
gMVP		0.67
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs104894363; hg19: chr12-111356964; COSMIC: COSV57407078; COSMIC: COSV57407078;