rs763783436

chr2-151607546-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_001164507.2(NEB):c.12597G>A(p.Pro4199=) variant causes a synonymous 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P4199P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 11)
  • Exomes 𝑓: 0.000063 (6 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.44

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.12597G>A	p.Pro4199=	synonymous_variant	83/182	ENST00000427231.7
NEB	NM_001164508.2	c.12597G>A	p.Pro4199=	synonymous_variant	83/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.12597G>A	p.Pro4199=	synonymous_variant	83/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.12597G>A	p.Pro4199=	synonymous_variant	83/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11601+2263G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 21 AN: 82006 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.000504

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000381

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000326

Gnomad OTH AF: 0.00101

GnomAD3 exomes AF: 0.000107 AC: 9 AN: 83810 Hom.: 0 AF XY: 0.0000660 AC XY: 3 AN XY: 45458

Gnomad AFR exome AF: 0.000682

Gnomad AMR exome AF: 0.000400

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000630 AC: 39 AN: 619498 Hom.: 6 Cov.: 7 AF XY: 0.0000565 AC XY: 18 AN XY: 318560

Gnomad4 AFR exome AF: 0.000511

Gnomad4 AMR exome AF: 0.000350

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000172

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000328

Gnomad4 OTH exome AF: 0.000134

GnomAD4 genome AF: 0.000256 AC: 21 AN: 82006 Hom.: 0 Cov.: 11 AF XY: 0.000233 AC XY: 9 AN XY: 38674

Gnomad4 AFR AF: 0.000504

Gnomad4 AMR AF: 0.000381

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000326

Gnomad4 OTH AF: 0.00101

Alfa AF: 0.000253 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 17, 2018

- -

Nemaline myopathy 2 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	6.5
Dann	Benign	0.24

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: rs763783436; hg19: chr2-152464060;