2-210293802-T-C

Variant names:

• chr2-210293802-T-C
• rs1559659233
• NM_079420.3:c.479-2A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_079420.3(MYL1):​c.479-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as no classifications from unflagged records (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYL1 NM_079420.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: no classifications from unflagged records no classifications from unflagged records P:1
• Conservation: PhyloP100: 7.84

Genes affected

MYL1 (HGNC:7582): (myosin light chain 1) Myosin is a hexameric ATPase cellular motor protein. It is composed of two heavy chains, two nonphosphorylatable alkali light chains, and two phosphorylatable regulatory light chains. This gene encodes a myosin alkali light chain expressed in fast skeletal muscle. Two transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13333334 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of -19, new splice context is: catggccttctttctgaaAGgag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-210293802-T-C is Pathogenic according to our data. Variant chr2-210293802-T-C is described in ClinVar as [no_classifications_from_unflagged_records]. Clinvar id is 627413.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1}. Variant chr2-210293802-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL1	NM_079420.3	c.479-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 6	ENST00000352451.4	NP_524144.1
MYL1	NM_079422.3	c.347-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 6		NP_524146.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYL1	ENST00000352451.4	c.479-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 6	1	NM_079420.3	ENSP00000307280.4
MYL1	ENST00000341685.8	c.347-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 6	1		ENSP00000343321.4
MYL1	ENST00000484290.1	n.610-2A>G		splice_acceptor_variant, intron_variant	Intron 5 of 5	5
MYL1	ENST00000496436.5	n.582-2A>G		splice_acceptor_variant, intron_variant	Intron 4 of 5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

Submissions by phenotype

Congenital myopathy with reduced type 2 muscle fibers Pathogenic:1

Jul 16, 2024

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.67		Position offset: 17
DS_AL_spliceai		0.97		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1559659233; hg19: chr2-211158526; COSMIC: COSV58974603;