rs2288206

Positions:

• chr2-151560550-G-A
• chr2-151560550-G-C

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.19314+42C>T 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 0.28 (6392 hom., cov: 27)
  • Exomes 𝑓: 0.26 (45134 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.447

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=-0.82).
• BP6: Variant 2-151560550-G-A is Benign according to our data. Variant chr2-151560550-G-A is described in ClinVar as [Benign]. Clinvar id is 257779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151560550-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.19314+42C>T		intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.19314+42C>T		intron_variant		ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.19314+42C>T		intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.19314+42C>T		intron_variant		5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 42660 AN: 150794 Hom.: 6387 Cov.: 27 FAILED QC

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.283

GnomAD3 exomes AF: 0.295 AC: 49242 AN: 166744 Hom.: 7800 AF XY: 0.286 AC XY: 25207 AN XY: 88240

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.336

Gnomad SAS exome AF: 0.185

Gnomad FIN exome AF: 0.297

Gnomad NFE exome AF: 0.283

Gnomad OTH exome AF: 0.306

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.259 AC: 332874 AN: 1284046 Hom.: 45134 Cov.: 19 AF XY: 0.257 AC XY: 164443 AN XY: 640206

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.397

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.357

Gnomad4 SAS exome AF: 0.185

Gnomad4 FIN exome AF: 0.289

Gnomad4 NFE exome AF: 0.253

Gnomad4 OTH exome AF: 0.270

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.283 AC: 42694 AN: 150912 Hom.: 6392 Cov.: 27 AF XY: 0.284 AC XY: 20920 AN XY: 73662

Gnomad4 AFR AF: 0.306

Gnomad4 AMR AF: 0.383

Gnomad4 ASJ AF: 0.238

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.273

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.280

Alfa AF: 0.267 Hom.: 942

Bravo AF: 0.297

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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

-

- -

Nemaline myopathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Arthrogryposis multiplex congenita 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.1
DANN	Benign	0.74

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: rs2288206; hg19: chr2-152417064; COSMIC: COSV50807678;