rs878924060

Positions:

• chr2-151617472-C-A
• chr2-151617472-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001164507.2(NEB):​c.11077-4G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 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 0.10 (0 hom., cov: 21)
  • Exomes 𝑓: 0.032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000008029
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.17

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-151617472-C-A is Benign according to our data. Variant chr2-151617472-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 283780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151617472-C-A is described in Lovd as [Benign]. Variant chr2-151617472-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.11077-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.11077-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.11077-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.11077-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.10348-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000386259
NEB	ENST00000486320.1	n.14G>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 8919 AN: 89130 Hom.: 0 Cov.: 21 FAILED QC

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.0433

Gnomad SAS AF: 0.0966

Gnomad FIN AF: 0.0402

Gnomad MID AF: 0.0474

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0873

GnomAD3 exomes AF: 0.113 AC: 4057 AN: 35788 Hom.: 0 AF XY: 0.117 AC XY: 2132 AN XY: 18152

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0870

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.0909

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.108

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0321 AC: 23078 AN: 719696 Hom.: 0 Cov.: 13 AF XY: 0.0346 AC XY: 12460 AN XY: 360516

Gnomad4 AFR exome AF: 0.0352

Gnomad4 AMR exome AF: 0.0559

Gnomad4 ASJ exome AF: 0.0447

Gnomad4 EAS exome AF: 0.0227

Gnomad4 SAS exome AF: 0.0749

Gnomad4 FIN exome AF: 0.0279

Gnomad4 NFE exome AF: 0.0288

Gnomad4 OTH exome AF: 0.0302

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.100 AC: 8919 AN: 89094 Hom.: 0 Cov.: 21 AF XY: 0.0933 AC XY: 4026 AN XY: 43134

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.0568

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.0436

Gnomad4 SAS AF: 0.0972

Gnomad4 FIN AF: 0.0402

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.0882

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 13, 2015	- -

Nemaline myopathy 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 29, 2019	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.3
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000080
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs878924060; hg19: chr2-152473986; COSMIC: COSV51417991;