rs546992311

chr2-151579593-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001164507.2(NEB):c.16449C>T(p.Ser5483=) 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (6 hom., cov: 8)
  • Exomes 𝑓: 0.0019 (61 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.303

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-151579593-G-A is Benign according to our data. Variant chr2-151579593-G-A is described in ClinVar as [Benign]. Clinvar id is 257761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.303 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 109 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.16449C>T	p.Ser5483=	synonymous_variant	105/182	ENST00000427231.7
NEB	NM_001164508.2	c.16449C>T	p.Ser5483=	synonymous_variant	105/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.16449C>T	p.Ser5483=	synonymous_variant	105/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.16449C>T	p.Ser5483=	synonymous_variant	105/182	5	NM_001164507.2	A2
NEB	ENST00000413693.5	c.639C>T	p.Ser213=	synonymous_variant	5/74	5
NEB	ENST00000409198.5	c.11602-3239C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 152 AN: 64802 Hom.: 7 Cov.: 8 FAILED QC

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0560

Gnomad SAS AF: 0.00449

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000109

Gnomad OTH AF: 0.00391

GnomAD3 exomes AF: 0.0139 AC: 551 AN: 39680 Hom.: 109 AF XY: 0.0138 AC XY: 278 AN XY: 20148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0697

Gnomad SAS exome AF: 0.00304

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000373

Gnomad OTH exome AF: 0.00893

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00191 AC: 2047 AN: 1072496 Hom.: 61 Cov.: 16 AF XY: 0.00189 AC XY: 1020 AN XY: 539308

Gnomad4 AFR exome AF: 0.000579

Gnomad4 AMR exome AF: 0.00926

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0328

Gnomad4 SAS exome AF: 0.00392

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000937

Gnomad4 OTH exome AF: 0.00468

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00230 AC: 149 AN: 64922 Hom.: 6 Cov.: 8 AF XY: 0.00249 AC XY: 74 AN XY: 29738

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00557

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0539

Gnomad4 SAS AF: 0.00450

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000109

Gnomad4 OTH AF: 0.00505

Alfa AF: 0.00160 Hom.: 0

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	Jul 08, 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	-	- -

Nemaline myopathy 2 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	8.7
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs546992311; hg19: chr2-152436107;