chr2-151630818-C-T

Position:

chr2-151630818-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001164508.2(NEB):c.9620G>A(p.Arg3207His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,587,284 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

NEB
NM_001164508.2 missense, splice_region

Scores

Splicing: ADA: 0.01420

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 0.0740

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044703454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.9620G>A	p.Arg3207His	missense_variant, splice_region_variant	67/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.9620G>A	p.Arg3207His	missense_variant, splice_region_variant	67/182	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.9620G>A	p.Arg3207His	missense_variant, splice_region_variant	67/182	5	NM_001164508.2	ENSP00000380505	P5	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.9620G>A	p.Arg3207His	missense_variant, splice_region_variant	67/182	5	NM_001164507.2	ENSP00000416578	A2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.8891G>A	p.Arg2964His	missense_variant, splice_region_variant	64/150	5		ENSP00000386259		P20929-4

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000202

AC:

AN:

223262

Hom.:

AF XY:

0.000266

AC XY:

AN XY:

120438

show subpopulations

Gnomad AFR exome

AF:

0.000207

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000793

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000580

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.000184

GnomAD4 exome

AF:

0.000205

AC:

294

AN:

1435162

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

157

AN XY:

712270

show subpopulations

Gnomad4 AFR exome

AF:

0.000154

Gnomad4 AMR exome

AF:

0.0000249

Gnomad4 ASJ exome

AF:

0.000794

Gnomad4 EAS exome

AF:

0.0000762

Gnomad4 SAS exome

AF:

0.000390

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000183

Gnomad4 OTH exome

AF:

0.000253

GnomAD4 genome

AF:

0.000125

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000195

Hom.:

Bravo

AF:

0.000178

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000243

AC:

ExAC

AF:

0.000191

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	NEB: PM2, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 13, 2023	BP4 -

Nemaline myopathy 2

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3207 of the NEB protein (p.Arg3207His). This variant is present in population databases (rs111841612, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 499819). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 04, 2024

Variant summary: NEB c.9620G>A (p.Arg3207His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 223262 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.0002 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.9620G>A in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 499819). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.8891G>A (p.R2964H) alteration is located in exon 64 (coding exon 62) of the NEB gene. This alteration results from a G to A substitution at nucleotide position 8891, causing the arginine (R) at amino acid position 2964 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.033

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

Eigen

Benign

0.11

Eigen_PC

Benign

-0.015

FATHMM_MKL

Benign

0.055

LIST_S2

Uncertain

0.88

D;T;T;T;D;.;.

M_CAP

Benign

0.030

MetaRNN

Benign

0.037

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

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.9

M;.;.;.;M;.;.

MutationTaster

Benign

0.85

D;D;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.1

N;N;.;N;N;.;.

REVEL

Benign

0.21

Sift

Benign

0.037

D;T;.;T;D;.;.

Sift4G

Uncertain

0.013

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

Polyphen

1.0

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

Vest4

0.16

MVP

0.50

MPC

0.070

ClinPred

0.11

GERP RS

3.8

Varity_R

0.17

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.014

dbscSNV1_RF

Benign

0.11

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