rs143123053

chr2-151687453-A-G

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.2603T>C(p.Leu868Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,614,038 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L868L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (18 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.97

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=0.030873865).
• BP6: Variant 2-151687453-A-G is Benign according to our data. Variant chr2-151687453-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 465592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151687453-A-G is described in Lovd as [Likely_benign]. Variant chr2-151687453-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00103 (157/152354) while in subpopulation EAS AF= 0.01 (52/5188). AF 95% confidence interval is 0.00785. There are 0 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.2603T>C	p.Leu868Pro	missense_variant	27/182	ENST00000427231.7
NEB	NM_001164508.2	c.2603T>C	p.Leu868Pro	missense_variant	27/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.2603T>C	p.Leu868Pro	missense_variant	27/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.2603T>C	p.Leu868Pro	missense_variant	27/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.2603T>C	p.Leu868Pro	missense_variant	27/150	5

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00621

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00156 AC: 389 AN: 249214 Hom.: 4 AF XY: 0.00132 AC XY: 178 AN XY: 135192

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00467

Gnomad EAS exome AF: 0.00812

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.00562

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00117 AC: 1716 AN: 1461684 Hom.: 18 Cov.: 31 AF XY: 0.00119 AC XY: 867 AN XY: 727120

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00459

Gnomad4 EAS exome AF: 0.0223

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.00517

Gnomad4 NFE exome AF: 0.000249

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00103 AC: 157 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74512

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.0100

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00621

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.000631

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000720 AC: 6

ExAC AF: 0.00149 AC: 180

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 03, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	NEB: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2021	This variant is associated with the following publications: (PMID: 25296583, 25589043) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D;D;D;D;D;.;.
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.031	T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	N;N;.;N;N;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.030	D;T;.;T;D;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		0.98	.;.;.;.;D;.;.
Vest4		0.96
MVP		0.71
MPC		0.42
ClinPred		0.052	T
GERP RS		5.5
Varity_R		0.74
gMVP		0.59

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: rs143123053; hg19: chr2-152543967;