2-151591331-G-GC

Position:

• chr2-151591331-G-GC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.14934+16_14934+17insG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (17 hom., cov: 19)
  • Exomes 𝑓: 0.26 (86 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.152

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 -16 ACMG points.

• BP6: Variant 2-151591331-G-GC is Benign according to our data. Variant chr2-151591331-G-GC is described in ClinVar as [Benign]. Clinvar id is 257749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.14934+16_14934+17insG		intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.14934+16_14934+17insG		intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.14934+16_14934+17insG		intron_variant		5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.14934+16_14934+17insG		intron_variant		5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.11602-14978_11602-14977insG		intron_variant		5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 28158 AN: 141824 Hom.: 18 Cov.: 19

Gnomad AFR AF: 0.0668

Gnomad AMI AF: 0.0826

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.240

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.211

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.261 AC: 344280 AN: 1319050 Hom.: 86 Cov.: 33 AF XY: 0.259 AC XY: 168847 AN XY: 651606

Gnomad4 AFR exome AF: 0.0636

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.201

Gnomad4 EAS exome AF: 0.236

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.257

Gnomad4 NFE exome AF: 0.276

Gnomad4 OTH exome AF: 0.242

GnomAD4 genome AF: 0.198 AC: 28165 AN: 141936 Hom.: 17 Cov.: 19 AF XY: 0.198 AC XY: 13710 AN XY: 69252

Gnomad4 AFR AF: 0.0669

Gnomad4 AMR AF: 0.223

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.251

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.208

Alfa AF: 0.186 Hom.: 1

Asia WGS AF: 0.205 AC: 713 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

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: rs11436831; hg19: chr2-152447845;