2-151640012-A-G

Position:

• chr2-151640012-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.8734T>C​(p.Ser2912Pro) variant causes a missense change. The variant allele was found at a frequency of 0.207 in 1,613,564 control chromosomes in the GnomAD database, including 49,168 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.31 (11054 hom., cov: 32)
  • Exomes 𝑓: 0.20 (38114 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.43

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=3.8599122E-5).
• BP6: Variant 2-151640012-A-G is Benign according to our data. Variant chr2-151640012-A-G is described in ClinVar as [Benign]. Clinvar id is 129761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151640012-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.8734T>C	p.Ser2912Pro	missense_variant	62/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.8734T>C	p.Ser2912Pro	missense_variant	62/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.8734T>C	p.Ser2912Pro	missense_variant	62/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.8734T>C	p.Ser2912Pro	missense_variant	62/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.8734T>C	p.Ser2912Pro	missense_variant	62/150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47545 AN: 151980 Hom.: 10994 Cov.: 32

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.289

GnomAD3 exomes AF: 0.243 AC: 60525 AN: 249014 Hom.: 10708 AF XY: 0.240 AC XY: 32451 AN XY: 135072

Gnomad AFR exome AF: 0.644

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.594

Gnomad SAS exome AF: 0.343

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.196 AC: 286005 AN: 1461466 Hom.: 38114 Cov.: 33 AF XY: 0.198 AC XY: 144180 AN XY: 727032

Gnomad4 AFR exome AF: 0.648

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.248

Gnomad4 EAS exome AF: 0.622

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.313 AC: 47659 AN: 152098 Hom.: 11054 Cov.: 32 AF XY: 0.310 AC XY: 23054 AN XY: 74360

Gnomad4 AFR AF: 0.630

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.258

Gnomad4 EAS AF: 0.607

Gnomad4 SAS AF: 0.335

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.298

Alfa AF: 0.199 Hom.: 10282

Bravo AF: 0.331

TwinsUK AF: 0.153 AC: 569

ALSPAC AF: 0.159 AC: 612

ESP6500AA AF: 0.598 AC: 2256

ESP6500EA AF: 0.165 AC: 1358

ExAC AF: 0.254 AC: 30680

Asia WGS AF: 0.546 AC: 1897 AN: 3478

EpiCase AF: 0.154

EpiControl AF: 0.160

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Ser2912Pro in exon 62 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 60% (2256/3774) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs6713162). -
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, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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 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.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 04, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2017	Variant summary: The NEB c.8734T>C (p.Ser2912Pro) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not working at the time of classification). This variant was found in 30671/120746 control chromosomes (5615 homozygotes) at a frequency of 0.2540126, which is approximately 72 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), evidence this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Arthrogryposis multiplex congenita 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.031
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	22
DANN	Benign	0.59
DEOGEN2	Benign	0.0032	.;.;T;.;T;.;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.58	T;T;T;T;T;.;.
MetaRNN	Benign	0.000039	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.8	N;N;.;N;N;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	2.9	N;N;.;N;N;.;.
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;.;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;B;.;.
Vest4		0.16
MPC		0.061
ClinPred		0.0072	T
GERP RS		5.5
Varity_R		0.20
gMVP		0.37

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: rs6713162; hg19: chr2-152496526; COSMIC: COSV50873704;