NM_001164507.2:c.3567+1G>C

Variant names:

• chr2-151677875-C-G
• rs587780399
• NM_001164507.2:c.3567+1G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001164507.2(NEB):​c.3567+1G>C variant causes a splice donor, 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEB NM_001164507.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91
• Publications: 1 publications found

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0121979825 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-151677875-C-G is Pathogenic according to our data. Variant chr2-151677875-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 558713.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151677875-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 558713.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151677875-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 558713.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151677875-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 558713.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151677875-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 558713.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151677875-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 558713.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151677875-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 558713.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.3567+1G>C		splice_donor_variant, intron_variant	Intron 33 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.3567+1G>C		splice_donor_variant, intron_variant	Intron 33 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.3567+1G>C		splice_donor_variant, intron_variant	Intron 33 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.3567+1G>C		splice_donor_variant, intron_variant	Intron 33 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.3567+1G>C		splice_donor_variant, intron_variant	Intron 33 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:1

Jun 06, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Arthrogryposis multiplex congenita 6 Pathogenic:1

Mar 09, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.9
GERP RS		5.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs587780399; hg19: chr2-152534389;