rs75807392

chr2-151659169-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):c.5971C>T(p.His1991Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0658 in 1,598,366 control chromosomes in the GnomAD database, including 5,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1991Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.054 (421 hom., cov: 32)
  • Exomes 𝑓: 0.067 (5061 hom.)
• Consequence: NEB NM_001164507.2 missense, splice_region
• Scores: Splicing: ADA: 0.0002484
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.47

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014465153).
• BP6: Variant 2-151659169-G-A is Benign according to our data. Variant chr2-151659169-G-A is described in ClinVar as [Benign]. Clinvar id is 129752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151659169-G-A is described in Lovd as [Likely_benign]. Variant chr2-151659169-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.5971C>T	p.His1991Tyr	missense_variant, splice_region_variant	47/182	ENST00000427231.7
NEB	NM_001164508.2	c.5971C>T	p.His1991Tyr	missense_variant, splice_region_variant	47/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.5971C>T	p.His1991Tyr	missense_variant, splice_region_variant	47/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.5971C>T	p.His1991Tyr	missense_variant, splice_region_variant	47/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.5971C>T	p.His1991Tyr	missense_variant, splice_region_variant	47/150	5

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 8278 AN: 151952 Hom.: 423 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0441

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0939

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.0411

GnomAD3 exomes AF: 0.0772 AC: 19116 AN: 247700 Hom.: 1208 AF XY: 0.0788 AC XY: 10586 AN XY: 134346

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0465

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.257

Gnomad SAS exome AF: 0.118

Gnomad FIN exome AF: 0.0990

Gnomad NFE exome AF: 0.0567

Gnomad OTH exome AF: 0.0675

GnomAD4 exome AF: 0.0670 AC: 96971 AN: 1446296 Hom.: 5061 Cov.: 29 AF XY: 0.0684 AC XY: 49242 AN XY: 720148

Gnomad4 AFR exome AF: 0.0163

Gnomad4 AMR exome AF: 0.0476

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.0978

Gnomad4 NFE exome AF: 0.0566

Gnomad4 OTH exome AF: 0.0689

GnomAD4 genome AF: 0.0544 AC: 8274 AN: 152070 Hom.: 421 Cov.: 32 AF XY: 0.0581 AC XY: 4318 AN XY: 74308

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.0442

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.271

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.0939

Gnomad4 NFE AF: 0.0545

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0585 Hom.: 613

Bravo AF: 0.0488

TwinsUK AF: 0.0539 AC: 200

ALSPAC AF: 0.0535 AC: 206

ESP6500AA AF: 0.0158 AC: 58

ESP6500EA AF: 0.0540 AC: 442

ExAC AF: 0.0772 AC: 9322

EpiCase AF: 0.0467

EpiControl AF: 0.0486

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.His1991Tyr in exon 47 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 5.4% (442/8180) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/) and in 26% (148/572) of Asian chromosomes by the 1000 Genomes Project (d bSNP rs75807392). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2017	Variant summary: The NEB c.5971C>T (p.His1991Tyr) variant involves the alteration of a non-conserved nucleotide that is the first exonic nucleotide at an exon-intron junction. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index) and 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 20328/251662 control chromosomes (1289 homozygotes) at a frequency of 0.080775, which is approximately 23 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), strongly suggesting this variant is likely a benign polymorphism. 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. -

Nemaline myopathy 2 Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Arthrogryposis multiplex congenita 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	19
Dann	Benign	0.44
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.12	T;T;T;T;T;.;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0014	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.;L;L;L;L
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	N;N;.;N;N;.;.
REVEL	Benign	0.049
Sift	Benign	1.0	T;T;.;T;T;.;.
Sift4G	Benign	0.077	T;D;D;D;T;D;D
Polyphen		0.68	.;.;.;.;P;.;.
Vest4		0.33
MPC		0.058
ClinPred		0.030	T
GERP RS		4.4
Varity_R		0.043
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.046
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

Other links and lift over

dbSNP: rs75807392; hg19: chr2-152515683; COSMIC: COSV51458616;