rs117270796

Variant names:

• chr2-151625525-T-C
• rs117270796
• NM_001164507.2:c.10452+9A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-151625525-T-C
• chr2-151625525-T-G

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.10452+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,558,288 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (54 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.881
• Publications: 1 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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-151625525-T-C is Benign according to our data. Variant chr2-151625525-T-C is described in ClinVar as Benign. ClinVar VariationId is 198369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00262 (399/152314) while in subpopulation EAS AF = 0.0539 (280/5190). AF 95% confidence interval is 0.0488. There are 10 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.10452+9A>G		intron_variant	Intron 71 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.10452+9A>G		intron_variant	Intron 71 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.10452+9A>G		intron_variant	Intron 71 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.10452+9A>G		intron_variant	Intron 71 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.9723+9A>G		intron_variant	Intron 68 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 403 AN: 152196 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0548

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00620 AC: 1434 AN: 231450 AF XY: 0.00569

Gnomad AFR exome AF: 0.000274

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0554

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000869

Gnomad OTH exome AF: 0.00333

GnomAD4 exome AF: 0.00190 AC: 2665 AN: 1405974 Hom.: 54 Cov.: 25 AF XY: 0.00186 AC XY: 1302 AN XY: 700266

African (AFR) AF: 0.000217 AC: 7 AN: 32300

American (AMR) AF: 0.0101 AC: 436 AN: 43004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25342

East Asian (EAS) AF: 0.0414 AC: 1619 AN: 39142

South Asian (SAS) AF: 0.00366 AC: 298 AN: 81370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51982

Middle Eastern (MID) AF: 0.000362 AC: 2 AN: 5532

European-Non Finnish (NFE) AF: 0.0000552 AC: 59 AN: 1069038

Other (OTH) AF: 0.00419 AC: 244 AN: 58264

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152314 Hom.: 10 Cov.: 33 AF XY: 0.00294 AC XY: 219 AN XY: 74484

African (AFR) AF: 0.000505 AC: 21 AN: 41572

American (AMR) AF: 0.00418 AC: 64 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0539 AC: 280 AN: 5190

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68014

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000888 Hom.: 1

Bravo AF: 0.00357

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 13, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 07, 2016

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.

Nemaline myopathy 2 Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

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.

not provided Benign:2

Jun 27, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 24, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NEB c.10452+9A>G variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 579/62270 control chromosomes (14 homozygotes) from ExAC at a frequency of 0.0092982, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is likely a benign polymorphism. The variant is more common in East Asian sub-population with allele frequency of 8.4% (382/4544 chromosomes). 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.3
DANN	Benign	0.86
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs117270796; hg19: chr2-152482039;