rs2288201

chr2-151547780-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):c.20158-42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,421,254 control chromosomes in the GnomAD database, including 288,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30717 hom., cov: 31)
  • Exomes 𝑓: 0.63 (257510 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.125

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-151547780-C-T is Benign according to our data. Variant chr2-151547780-C-T is described in ClinVar as [Benign]. Clinvar id is 257783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151547780-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.20158-42G>A		intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.20158-42G>A		intron_variant		ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.20158-42G>A		intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.20158-42G>A		intron_variant		5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96048 AN: 151646 Hom.: 30670 Cov.: 31

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.716

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.771

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.676

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.639

GnomAD3 exomes AF: 0.642 AC: 133760 AN: 208318 Hom.: 43444 AF XY: 0.631 AC XY: 70575 AN XY: 111840

Gnomad AFR exome AF: 0.610

Gnomad AMR exome AF: 0.752

Gnomad ASJ exome AF: 0.540

Gnomad EAS exome AF: 0.777

Gnomad SAS exome AF: 0.491

Gnomad FIN exome AF: 0.665

Gnomad NFE exome AF: 0.635

Gnomad OTH exome AF: 0.649

GnomAD4 exome AF: 0.635 AC: 805915 AN: 1269490 Hom.: 257510 Cov.: 17 AF XY: 0.629 AC XY: 400223 AN XY: 636424

Gnomad4 AFR exome AF: 0.611

Gnomad4 AMR exome AF: 0.741

Gnomad4 ASJ exome AF: 0.532

Gnomad4 EAS exome AF: 0.793

Gnomad4 SAS exome AF: 0.491

Gnomad4 FIN exome AF: 0.664

Gnomad4 NFE exome AF: 0.638

Gnomad4 OTH exome AF: 0.633

GnomAD4 genome AF: 0.634 AC: 96156 AN: 151764 Hom.: 30717 Cov.: 31 AF XY: 0.636 AC XY: 47186 AN XY: 74148

Gnomad4 AFR AF: 0.604

Gnomad4 AMR AF: 0.716

Gnomad4 ASJ AF: 0.532

Gnomad4 EAS AF: 0.770

Gnomad4 SAS AF: 0.502

Gnomad4 FIN AF: 0.676

Gnomad4 NFE AF: 0.632

Gnomad4 OTH AF: 0.644

Alfa AF: 0.632 Hom.: 5644

Bravo AF: 0.640

Asia WGS AF: 0.630 AC: 2193 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

-

- -

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	-0.90
Cadd	Benign	1.6
Dann	Benign	0.71

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: rs2288201; hg19: chr2-152404294;