chr2-151579326-C-G

Position:

• chr2-151579326-C-G

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.16704+12G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (7602 hom., cov: 18)
  • Exomes 𝑓: 0.098 (38950 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.25

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=-0.84).
• BP6: Variant 2-151579326-C-G is Benign according to our data. Variant chr2-151579326-C-G is described in ClinVar as [Benign]. Clinvar id is 257766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151579326-C-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.16704+12G>C		intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.16704+12G>C		intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.16704+12G>C		intron_variant		5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.16704+12G>C		intron_variant		5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.11602-2972G>C		intron_variant		5		ENSP00000386259
NEB	ENST00000413693.5	c.894+12G>C		intron_variant		5		ENSP00000410961

Frequencies

GnomAD3 genomes AF: 0.00 AC: 33722 AN: 100138 Hom.: 7608 Cov.: 18 FAILED QC

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.526

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.323

GnomAD3 exomes AF: 0.0314 AC: 3303 AN: 105038 Hom.: 1632 AF XY: 0.0309 AC XY: 1750 AN XY: 56554

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.00402

Gnomad EAS exome AF: 0.0665

Gnomad SAS exome AF: 0.0265

Gnomad FIN exome AF: 0.00415

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0399

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0985 AC: 83454 AN: 847584 Hom.: 38950 Cov.: 29 AF XY: 0.103 AC XY: 43130 AN XY: 418696

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.0907

Gnomad4 EAS exome AF: 0.347

Gnomad4 SAS exome AF: 0.0997

Gnomad4 FIN exome AF: 0.314

Gnomad4 NFE exome AF: 0.0792

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.336 AC: 33695 AN: 100218 Hom.: 7602 Cov.: 18 AF XY: 0.324 AC XY: 15374 AN XY: 47378

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.469

Gnomad4 ASJ AF: 0.353

Gnomad4 EAS AF: 0.455

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.328

Gnomad4 NFE AF: 0.485

Gnomad4 OTH AF: 0.316

Alfa AF: 0.278 Hom.: 778

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.78

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: rs62174689; hg19: chr2-152435840; COSMIC: COSV51458385;