rs41270201

Variant names:

• chr2-151508075-G-A
• rs41270201
• NM_001164507.2:c.23381C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.23381C>T​(p.Ser7794Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,609,282 control chromosomes in the GnomAD database, including 531 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. S7794S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (24 hom., cov: 33)
  • Exomes 𝑓: 0.024 (507 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 9.35
• Publications: 8 publications found

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]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008599877).
• BP6: Variant 2-151508075-G-A is Benign according to our data. Variant chr2-151508075-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0164 (2497/152236) while in subpopulation NFE AF = 0.027 (1838/68028). AF 95% confidence interval is 0.026. There are 24 homozygotes in GnomAd4. There are 1126 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.23381C>T	p.Ser7794Leu	missense_variant	Exon 162 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.23381C>T	p.Ser7794Leu	missense_variant	Exon 162 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.23381C>T	p.Ser7794Leu	missense_variant	Exon 162 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.23381C>T	p.Ser7794Leu	missense_variant	Exon 162 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2497 AN: 152118 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0175 AC: 4228 AN: 242286 AF XY: 0.0174

Gnomad AFR exome AF: 0.00484

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.00194

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0237 AC: 34500 AN: 1457046 Hom.: 507 Cov.: 30 AF XY: 0.0230 AC XY: 16637 AN XY: 724446

African (AFR) AF: 0.00338 AC: 113 AN: 33436

American (AMR) AF: 0.0124 AC: 551 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.00255 AC: 66 AN: 25918

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39654

South Asian (SAS) AF: 0.00137 AC: 117 AN: 85252

European-Finnish (FIN) AF: 0.0270 AC: 1435 AN: 53196

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5764

European-Non Finnish (NFE) AF: 0.0281 AC: 31142 AN: 1109276

Other (OTH) AF: 0.0176 AC: 1060 AN: 60202

GnomAD4 genome AF: 0.0164 AC: 2497 AN: 152236 Hom.: 24 Cov.: 33 AF XY: 0.0151 AC XY: 1126 AN XY: 74418

African (AFR) AF: 0.00453 AC: 188 AN: 41536

American (AMR) AF: 0.0137 AC: 209 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.0197 AC: 209 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0270 AC: 1838 AN: 68028

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0244 Hom.: 196

Bravo AF: 0.0158

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00597 AC: 22

ESP6500EA AF: 0.0272 AC: 223

ExAC AF: 0.0176 AC: 2121

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser7829Leu in exon 163 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 2.7% (223/8186) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs41270201). -

Dec 22, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Jun 24, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NEB c.23486C>T (p.Ser7829Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.017 in 242286 control chromosomes in the gnomAD database, including 50 homozygotes. The observed variant frequency is approximately 5-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in NEB causing Nemaline Myopathy 2 phenotype (0.0035), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.23486C>T in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

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PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nemaline myopathy 2 Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;T;.;D;T;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;.;.
MetaRNN	Benign	0.0086	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M;.;.;.
PhyloP100		9.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.3	D;D;.;D;D;D;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.020	D;T;.;T;D;T;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.;.
Vest4		0.46
MPC		0.25
ClinPred		0.0096	T
GERP RS		5.3
PromoterAI		-0.026	Neutral
Varity_R		0.28
gMVP		0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41270201; hg19: chr2-152364589;