rs1131692323

Positions:

• chr12-110911091-C-G
• chr12-110911091-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000432.4(MYL2):​c.487G>C​(p.Glu163Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E163A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYL2 NM_000432.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.81

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000432.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-110911090-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43480.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYL2	NM_000432.4	c.487G>C	p.Glu163Gln	missense_variant	7/7	ENST00000228841.15
MYL2	NM_001406745.1	c.445G>C	p.Glu149Gln	missense_variant	6/6
MYL2	NM_001406916.1	c.430G>C	p.Glu144Gln	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYL2	ENST00000228841.15	c.487G>C	p.Glu163Gln	missense_variant	7/7	1	NM_000432.4	P1
MYL2	ENST00000548438.1	c.445G>C	p.Glu149Gln	missense_variant	6/6	3
MYL2	ENST00000663220.1	c.430G>C	p.Glu144Gln	missense_variant	7/7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Nov 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
CardioboostCm	Uncertain	0.78
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.29
Sift	Benign	0.38	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.99	D;.
Vest4		0.52
MutPred		0.23		Gain of catalytic residue at H161 (P = 0.0224);.;
MVP		0.86
MPC		1.1
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.45
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131692323; hg19: chr12-111348895;