rs36105240

Positions:

chr2-151710447-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_001164507.2(NEB):c.914A>G(p.Asp305Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,611,260 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D305D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0019 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 35 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.75

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 -15 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 2-151710447-T-C is Benign according to our data. Variant chr2-151710447-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 193880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00188 (286/152314) while in subpopulation EAS AF= 0.0232 (120/5178). AF 95% confidence interval is 0.0198. There are 4 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.914A>G	p.Asp305Gly	missense_variant	11/182	ENST00000427231.7
NEB	NM_001164508.2 linkuse as main transcript	c.914A>G	p.Asp305Gly	missense_variant	11/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.914A>G	p.Asp305Gly	missense_variant	11/182	5	NM_001164508.2	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.914A>G	p.Asp305Gly	missense_variant	11/182	5	NM_001164507.2	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.914A>G	p.Asp305Gly	missense_variant	11/150	5			P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

286

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.0231

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0108

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00321

AC:

798

AN:

248910

Hom.:

AF XY:

0.00294

AC XY:

397

AN XY:

135020

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.0191

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.0113

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.00298

GnomAD4 exome

AF:

0.00170

AC:

2474

AN:

1458946

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

1196

AN XY:

725936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00234

Gnomad4 EAS exome

AF:

0.0338

Gnomad4 SAS exome

AF:

0.000349

Gnomad4 FIN exome

AF:

0.0108

Gnomad4 NFE exome

AF:

0.000297

Gnomad4 OTH exome

AF:

0.00219

GnomAD4 genome

AF:

0.00188

AC:

286

AN:

152314

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

175

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.0232

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0108

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000929

Hom.:

Bravo

AF:

0.00100

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000362

AC:

ExAC

AF:

0.00348

AC:

421

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 24, 2018	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2022	Variant summary: NEB c.914A>G (p.Asp305Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 248910 control chromosomes, predominantly at a frequency of 0.019 within the East Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in NEB causing Nemaline Myopathy 2 phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.914A>G in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2014	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2020

This variant is associated with the following publications: (PMID: 28391287) -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Uncertain

DANN

Benign

0.92

DEOGEN2

Benign

0.060

.;.;T;.;T;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.89

D;D;D;D;D;.;.

MetaRNN

Benign

0.0076

T;T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

L;L;.;L;L;L;L

MutationTaster

Benign

0.92

N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.2

N;D;.;D;N;.;.

REVEL

Benign

0.078

Sift

Benign

0.20

T;T;.;T;T;.;.

Sift4G

Uncertain

0.0040

D;D;D;D;D;D;D

Polyphen

0.032

.;.;.;.;B;.;.

Vest4

0.46

MVP

0.34

MPC

0.14

ClinPred

0.038

GERP RS

4.5

Varity_R

0.16

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.75

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.75

Position offset: 1

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