rs184262608

chr2-151659071-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):c.6069G>A(p.Met2023Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00826 in 1,596,242 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2023V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0065 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (66 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.968

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=0.011434644).
• BP6: Variant 2-151659071-C-T is Benign according to our data. Variant chr2-151659071-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151659071-C-T is described in Lovd as [Benign]. Variant chr2-151659071-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00648 (987/152244) while in subpopulation NFE AF= 0.0105 (714/68030). AF 95% confidence interval is 0.00986. There are 8 homozygotes in gnomad4. There are 485 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.6069G>A	p.Met2023Ile	missense_variant	47/182	ENST00000427231.7
NEB	NM_001164508.2	c.6069G>A	p.Met2023Ile	missense_variant	47/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.6069G>A	p.Met2023Ile	missense_variant	47/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.6069G>A	p.Met2023Ile	missense_variant	47/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.6069G>A	p.Met2023Ile	missense_variant	47/150	5

Frequencies

GnomAD3 genomes AF: 0.00649 AC: 987 AN: 152126 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00764

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00642 AC: 1598 AN: 248750 Hom.: 7 AF XY: 0.00640 AC XY: 864 AN XY: 134922

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00808

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00779

GnomAD4 exome AF: 0.00845 AC: 12198 AN: 1443998 Hom.: 66 Cov.: 29 AF XY: 0.00828 AC XY: 5958 AN XY: 719402

Gnomad4 AFR exome AF: 0.00139

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00354

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00770

Gnomad4 NFE exome AF: 0.0100

Gnomad4 OTH exome AF: 0.00737

GnomAD4 genome AF: 0.00648 AC: 987 AN: 152244 Hom.: 8 Cov.: 32 AF XY: 0.00652 AC XY: 485 AN XY: 74428

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00764

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00935 Hom.: 12

Bravo AF: 0.00568

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00134 AC: 5

ESP6500EA AF: 0.00999 AC: 82

ExAC AF: 0.00650 AC: 785

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00939

EpiControl AF: 0.00842

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	GeneDx	Aug 03, 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	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -

not provided Benign:3

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	Athena Diagnostics	May 07, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NEB: BS1, BS2 -

Nemaline myopathy 2 Benign:3

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	19
Dann	Benign	0.87
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.67	T;T;T;T;T;.;.
MetaRNN	Benign	0.011	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.28	N;N;.;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.89	N;N;.;N;N;.;.
REVEL	Benign	0.13
Sift	Benign	1.0	T;T;.;T;T;.;.
Sift4G	Benign	0.94	T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;B;.;.
Vest4		0.25
MutPred		0.60		Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.25
MPC		0.056
ClinPred		0.012	T
GERP RS		5.2
Varity_R		0.29
gMVP		0.21

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: rs184262608; hg19: chr2-152515585;