rs200545007

Positions:

• chr2-151666287-G-A
• chr2-151666287-G-T

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.4834C>T​(p.Arg1612Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000464 in 1,613,854 control chromosomes in the GnomAD database, including 3 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R1612H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 4.82

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=0.03369087).
• BP6: Variant 2-151666287-G-A is Benign according to our data. Variant chr2-151666287-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 74142.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}. Variant chr2-151666287-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00127 (193/152188) while in subpopulation AFR AF= 0.00296 (123/41530). AF 95% confidence interval is 0.00254. There are 3 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.4834C>T	p.Arg1612Cys	missense_variant	41/182	ENST00000427231.7
NEB	NM_001164508.2	c.4834C>T	p.Arg1612Cys	missense_variant	41/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.4834C>T	p.Arg1612Cys	missense_variant	41/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.4834C>T	p.Arg1612Cys	missense_variant	41/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.4834C>T	p.Arg1612Cys	missense_variant	41/150	5

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 191 AN: 152070 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.000618 AC: 154 AN: 249142 Hom.: 0 AF XY: 0.000503 AC XY: 68 AN XY: 135144

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000434

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000380 AC: 556 AN: 1461666 Hom.: 0 Cov.: 31 AF XY: 0.000344 AC XY: 250 AN XY: 727120

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000318

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152188 Hom.: 3 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74408

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000445 Hom.: 0

Bravo AF: 0.00144

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00253 AC: 10

ESP6500EA AF: 0.000480 AC: 4

ExAC AF: 0.000538 AC: 65

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2020	This variant is associated with the following publications: (PMID: 23887774, 23167750) -

Nemaline myopathy 2 Uncertain:1 Benign:2

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.4834C>T (p.R1612C) alteration is located in exon 41 (coding exon 39) of the NEB gene. This alteration results from a C to T substitution at nucleotide position 4834, causing the arginine (R) at amino acid position 1612 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

NEB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 14, 2021

This variant is classified as likely 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	0.32
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;.
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.034	T;T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.3	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.8	D;D;.;D;D;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D;D;.;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.55
MVP		0.76
MPC		0.38
ClinPred		0.069	T
GERP RS		5.8
Varity_R		0.32
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200545007; hg19: chr2-152522801; COSMIC: COSV51102728; COSMIC: COSV51102728;