rs149025191

chr2-151617397-C-Gchr2-151617397-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.11148G>C(p.Met3716Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,564,866 control chromosomes in the GnomAD database, including 269 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M3716T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (29 hom., cov: 31)
  • Exomes 𝑓: 0.016 (240 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.485

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=0.006017059).
• BP6: Variant 2-151617397-C-G is Benign according to our data. Variant chr2-151617397-C-G is described in ClinVar as [Benign]. Clinvar id is 129706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151617397-C-G is described in Lovd as [Benign]. Variant chr2-151617397-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0136 (2035/149722) while in subpopulation NFE AF= 0.0185 (1257/67786). AF 95% confidence interval is 0.0177. There are 29 homozygotes in gnomad4. There are 1043 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.11148G>C	p.Met3716Ile	missense_variant	75/182	ENST00000427231.7
NEB	NM_001164508.2	c.11148G>C	p.Met3716Ile	missense_variant	75/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.11148G>C	p.Met3716Ile	missense_variant	75/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.11148G>C	p.Met3716Ile	missense_variant	75/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.10419G>C	p.Met3473Ile	missense_variant	72/150	5
NEB	ENST00000486320.1	n.89G>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2037 AN: 149610 Hom.: 29 Cov.: 31

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.0144

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00896

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0145

GnomAD3 exomes AF: 0.0135 AC: 2609 AN: 192764 Hom.: 28 AF XY: 0.0143 AC XY: 1465 AN XY: 102778

Gnomad AFR exome AF: 0.00235

Gnomad AMR exome AF: 0.00726

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.0000679

Gnomad SAS exome AF: 0.0171

Gnomad FIN exome AF: 0.0299

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0161

GnomAD4 exome AF: 0.0162 AC: 22937 AN: 1415144 Hom.: 240 Cov.: 31 AF XY: 0.0162 AC XY: 11347 AN XY: 700108

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.00822

Gnomad4 ASJ exome AF: 0.0111

Gnomad4 EAS exome AF: 0.0000262

Gnomad4 SAS exome AF: 0.0156

Gnomad4 FIN exome AF: 0.0303

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0136 AC: 2035 AN: 149722 Hom.: 29 Cov.: 31 AF XY: 0.0143 AC XY: 1043 AN XY: 72936

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.00896

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.0325

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.0143

Alfa AF: 0.0151 Hom.: 18

Bravo AF: 0.0112

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.00346 AC: 13

ESP6500EA AF: 0.0178 AC: 146

ExAC AF: 0.00932 AC: 1106

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 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. -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Nemaline myopathy 2 Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.87	D;T;T;T;D;.;.
MetaRNN	Benign	0.0060	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.33	N;.;.;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N;N;.;N;N;.;.
REVEL	Benign	0.11
Sift	Benign	0.41	T;T;.;T;T;.;.
Sift4G	Uncertain	0.049	D;T;T;T;D;T;T
Polyphen		0.060	.;.;.;.;B;.;.
Vest4		0.39
MutPred		0.52		Loss of ubiquitination at K3476 (P = 0.0957);.;.;.;Loss of ubiquitination at K3476 (P = 0.0957);.;.;
MPC		0.061
ClinPred		0.018	T
GERP RS		5.2
Varity_R		0.23
gMVP		0.11

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: rs149025191; hg19: chr2-152473911; COSMIC: COSV50807099;