2-151618284-G-A

Position:

chr2-151618284-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP7BS1

This summary comes from the ClinGen Evidence Repository: The c.11067C>T is a synonymous (silent) variant (p.Asn3689=) that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the UCSC Genome Browser (BP4, BP7). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.0006878 (922/1461502 alleles, 2 homozygotes) in the non-Finnish European population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (MAF ≥ 0.000237) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive congenital myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathy VCEP: BS1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA1908888/MONDO:0018958/146

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 2 hom. )

Consequence

NEB
NM_001164508.2 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel B:5

Conservation

PhyloP100: -1.92

Variant links:

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]

NEB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.11067C>T	p.Asn3689Asn	synonymous_variant	74/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.11067C>T	p.Asn3689Asn	synonymous_variant	74/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.11067C>T	p.Asn3689Asn	synonymous_variant	74/182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.11067C>T	p.Asn3689Asn	synonymous_variant	74/182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.10338C>T	p.Asn3446Asn	synonymous_variant	71/150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000511

AC XY:

AN XY:

134914

show subpopulations

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.:

Cov.:

AF XY:

0.000615

AC XY:

447

AN XY:

727072

show subpopulations

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:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74332

show subpopulations

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.:

Bravo

AF:

0.000276

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000711

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

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

NEB-related disorder

Benign:1

Likely benign, no assertion criteria provided

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

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Aug 07, 2024

The c.11067C>T is a synonymous (silent) variant (p.Asn3689=) that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the UCSC Genome Browser (BP4, BP7). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.0006878 (922/1461502 alleles, 2 homozygotes) in the non-Finnish European population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (MAF ≥ 0.000237) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive congenital myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathy VCEP: BS1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) -

Nemaline myopathy 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over