rs762368980

chr2-151546003-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS2

The NM_001164507.2(NEB):c.20467-5T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000442 in 1,243,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: NEB NM_001164507.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0008130
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.940

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]

LOC124906081 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-151546003-A-T is Benign according to our data. Variant chr2-151546003-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 465540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 104 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.20467-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.20467-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000397345.8
LOC124906081	XR_007087266.1	n.5990-1317A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.20467-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.20467-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00000708 AC: 1 AN: 141244 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00368 AC: 379 AN: 103110 Hom.: 104 AF XY: 0.00338 AC XY: 188 AN XY: 55702

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.00456

Gnomad ASJ exome AF: 0.00311

Gnomad EAS exome AF: 0.00383

Gnomad SAS exome AF: 0.00384

Gnomad FIN exome AF: 0.00160

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.000498 AC: 549 AN: 1101890 Hom.: 0 Cov.: 19 AF XY: 0.000528 AC XY: 291 AN XY: 551290

Gnomad4 AFR exome AF: 0.0000463

Gnomad4 AMR exome AF: 0.000572

Gnomad4 ASJ exome AF: 0.000692

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000213

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.000568

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.00000708 AC: 1 AN: 141244 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 68964

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NEB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 03, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nemaline myopathy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	5.0
Dann	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00081
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.090		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: rs762368980; hg19: chr2-152402517;