rs200427401

Positions:

• chr2-151618284-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_001164507.2(NEB):​c.11067C>T​(p.Asn3689=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000612 in 1,613,674 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (2 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.92

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 2-151618284-G-A is Benign according to our data. Variant chr2-151618284-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 389787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.92 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.11067C>T	p.Asn3689=	synonymous_variant	74/182	ENST00000427231.7
NEB	NM_001164508.2	c.11067C>T	p.Asn3689=	synonymous_variant	74/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.11067C>T	p.Asn3689=	synonymous_variant	74/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.11067C>T	p.Asn3689=	synonymous_variant	74/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.10338C>T	p.Asn3446=	synonymous_variant	71/150	5

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000450 AC: 112 AN: 248706 Hom.: 0 AF XY: 0.000511 AC XY: 69 AN XY: 134914

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.000675

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000631 AC: 922 AN: 1461502 Hom.: 2 Cov.: 31 AF XY: 0.000615 AC XY: 447 AN XY: 727072

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000899

Gnomad4 NFE exome AF: 0.000730

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74332

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000564 Hom.: 0

Bravo AF: 0.000276

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000711

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	NEB: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2020	- -

NEB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 15, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nemaline myopathy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.5
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200427401; hg19: chr2-152474798;