rs145052299

Positions:

chr2-151627005-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001164507.2(NEB):c.10344C>T(p.Asn3448=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,613,800 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 67 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.761

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 Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 2-151627005-G-A is Benign according to our data. Variant chr2-151627005-G-A is described in ClinVar as [Benign]. Clinvar id is 257717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151627005-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.761 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00881 (1342/152246) while in subpopulation EAS AF= 0.0523 (271/5182). AF 95% confidence interval is 0.0472. There are 10 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.10344C>T	p.Asn3448=	synonymous_variant	70/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.10344C>T	p.Asn3448=	synonymous_variant	70/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.10344C>T	p.Asn3448=	synonymous_variant	70/182	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.10344C>T	p.Asn3448=	synonymous_variant	70/182	5	NM_001164507.2	ENSP00000416578	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.9615C>T	p.Asn3205=	synonymous_variant	67/150	5		ENSP00000386259		P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00880

AC:

1339

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0221

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00675

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0531

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00769

AC:

1916

AN:

249046

Hom.:

AF XY:

0.00682

AC XY:

922

AN XY:

135104

show subpopulations

Gnomad AFR exome

AF:

0.0231

Gnomad AMR exome

AF:

0.0121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0548

Gnomad SAS exome

AF:

0.00376

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00447

GnomAD4 exome

AF:

0.00255

AC:

3733

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1776

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.0238

Gnomad4 AMR exome

AF:

0.0113

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0407

Gnomad4 SAS exome

AF:

0.00369

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000114

Gnomad4 OTH exome

AF:

0.00570

GnomAD4 genome

AF:

0.00881

AC:

1342

AN:

152246

Hom.:

Cov.:

AF XY:

0.00907

AC XY:

675

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0222

Gnomad4 AMR

AF:

0.00674

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0523

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00383

Hom.:

Bravo

AF:

0.0111

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2017	Variant summary: The NEB c.10344C>T (p.Asn3448Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 925/120696 control chromosomes (19 homozygotes) at a frequency of 0.0076639, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is likely a benign polymorphism. The variant is more common in East Asian sub-population with allele frequency of 5.4% (464/8592 chromosomes). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 27, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nemaline myopathy 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.4

DANN

Benign

0.55

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

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