rs35686968

Positions:

• chr2-151724301-C-G

Variant summary

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

The NM_001164508.2(NEB):​c.571G>C​(p.Glu191Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,613,012 control chromosomes in the GnomAD database, including 553 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.016 (44 hom., cov: 31)
  • Exomes 𝑓: 0.024 (509 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 7.49

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=0.010740876).
• BP6: Variant 2-151724301-C-G is Benign according to our data. Variant chr2-151724301-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129748.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=8}. Variant chr2-151724301-C-G is described in Lovd as [Benign]. Variant chr2-151724301-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.016 (2429/152182) while in subpopulation NFE AF= 0.0259 (1759/68010). AF 95% confidence interval is 0.0249. There are 44 homozygotes in gnomad4. There are 1148 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.571G>C	p.Glu191Gln	missense_variant	8/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.571G>C	p.Glu191Gln	missense_variant	8/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.571G>C	p.Glu191Gln	missense_variant	8/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.571G>C	p.Glu191Gln	missense_variant	8/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.571G>C	p.Glu191Gln	missense_variant	8/150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2429 AN: 152064 Hom.: 44 Cov.: 31

Gnomad AFR AF: 0.00488

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00976

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.0163 AC: 4051 AN: 248062 Hom.: 68 AF XY: 0.0172 AC XY: 2310 AN XY: 134512

Gnomad AFR exome AF: 0.00408

Gnomad AMR exome AF: 0.00531

Gnomad ASJ exome AF: 0.00409

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.0239 AC: 34883 AN: 1460830 Hom.: 509 Cov.: 30 AF XY: 0.0236 AC XY: 17122 AN XY: 726580

Gnomad4 AFR exome AF: 0.00341

Gnomad4 AMR exome AF: 0.00587

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.0213

Gnomad4 NFE exome AF: 0.0280

Gnomad4 OTH exome AF: 0.0204

GnomAD4 genome AF: 0.0160 AC: 2429 AN: 152182 Hom.: 44 Cov.: 31 AF XY: 0.0154 AC XY: 1148 AN XY: 74368

Gnomad4 AFR AF: 0.00486

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00977

Gnomad4 FIN AF: 0.0210

Gnomad4 NFE AF: 0.0259

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.0233 Hom.: 39

Bravo AF: 0.0142

TwinsUK AF: 0.0272 AC: 101

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00503 AC: 20

ESP6500EA AF: 0.0255 AC: 212

ExAC AF: 0.0163 AC: 1974

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0220

EpiControl AF: 0.0225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 06, 2018	Variant summary: NEB c.571G>C (p.Glu191Gln) results in a conservative amino acid change located in the Nebulin repeat region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.016 in 276052 control chromosomes in the gnomAD database, including 81 homozygotes. The observed variant frequency is approximately 4.65 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 benign. To our knowledge, no occurrence of c.571G>C in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites variant as "benign." Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 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. -

Nemaline myopathy 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, 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 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.	Jun 08, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	NEB: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	.;.;T;.;T;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;.;.
MetaRNN	Benign	0.011	T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.6	L;L;.;L;L;L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.2	N;N;.;N;N;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.19	T;T;.;T;T;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.72
MPC		0.34
ClinPred		0.013	T
GERP RS		6.0
Varity_R		0.34
gMVP		0.56

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: rs35686968; hg19: chr2-152580815;