rs146616621

Positions:

• chr2-151677746-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001164507.2(NEB):​c.3593A>G​(p.Asn1198Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,613,934 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (7 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: -1.32

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005604297).
• BP6: Variant 2-151677746-T-C is Benign according to our data. Variant chr2-151677746-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211587.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=3}. Variant chr2-151677746-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00203 (309/152292) while in subpopulation AMR AF= 0.00321 (49/15286). AF 95% confidence interval is 0.00249. There are 0 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.3593A>G	p.Asn1198Ser	missense_variant	34/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.3593A>G	p.Asn1198Ser	missense_variant	34/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.3593A>G	p.Asn1198Ser	missense_variant	34/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.3593A>G	p.Asn1198Ser	missense_variant	34/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.3593A>G	p.Asn1198Ser	missense_variant	34/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00233 AC: 581 AN: 249234 Hom.: 1 AF XY: 0.00244 AC XY: 330 AN XY: 135208

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00914

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.00289

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00281 AC: 4103 AN: 1461642 Hom.: 7 Cov.: 31 AF XY: 0.00276 AC XY: 2007 AN XY: 727102

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.00804

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00309

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74480

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00259

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00319 Hom.: 0

Bravo AF: 0.00249

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.00303 AC: 25

ExAC AF: 0.00213 AC: 257

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	This variant is associated with the following publications: (PMID: 25888430) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NEB: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Nemaline myopathy 2 Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 14, 2014	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.3593A>G (p.N1198S) alteration is located in exon 34 (coding exon 32) of the NEB gene. This alteration results from a A to G substitution at nucleotide position 3593, causing the asparagine (N) at amino acid position 1198 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

NEB-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.6
DANN	Benign	0.92
DEOGEN2	Benign	0.020	.;.;T;.;T;.;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.59	T;T;T;T;T;.;.
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0056	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.98	L;L;.;L;L;L;L
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.68	N;N;.;N;N;.;.
REVEL	Benign	0.044
Sift	Benign	0.27	T;T;.;T;T;.;.
Sift4G	Benign	0.22	T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;B;.;.
Vest4		0.088
MVP		0.27
MPC		0.050
ClinPred		0.0027	T
GERP RS		-0.32
Varity_R		0.037
gMVP		0.34

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

Other links and lift over

dbSNP: rs146616621; hg19: chr2-152534260;