NM_001164507.2:c.612+8T>C

Variant names:

• chr2-151724252-A-G
• rs113095802
• NM_001164507.2:c.612+8T>C

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.612+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,605,928 control chromosomes in the GnomAD database, including 372 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (60 hom., cov: 31)
  • Exomes 𝑓: 0.018 (312 hom.)
• Consequence: NEB NM_001164507.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002785
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.343
• Publications: 5 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=-0.83).
• BP6: Variant 2-151724252-A-G is Benign according to our data. Variant chr2-151724252-A-G is described in ClinVar as Benign. ClinVar VariationId is 129753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0235 (3584/152198) while in subpopulation AFR AF = 0.0397 (1650/41538). AF 95% confidence interval is 0.0381. There are 60 homozygotes in GnomAd4. There are 1712 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 60 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.612+8T>C		splice_region_variant, intron_variant	Intron 8 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.612+8T>C		splice_region_variant, intron_variant	Intron 8 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.612+8T>C		splice_region_variant, intron_variant	Intron 8 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.612+8T>C		splice_region_variant, intron_variant	Intron 8 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.612+8T>C		splice_region_variant, intron_variant	Intron 8 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3570 AN: 152080 Hom.: 60 Cov.: 31

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0430

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.0239

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0269

GnomAD2 exomes AF: 0.0186 AC: 4556 AN: 244552 AF XY: 0.0194

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.00822

Gnomad ASJ exome AF: 0.0468

Gnomad EAS exome AF: 0.00417

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0183 AC: 26561 AN: 1453730 Hom.: 312 Cov.: 29 AF XY: 0.0187 AC XY: 13496 AN XY: 723124

African (AFR) AF: 0.0429 AC: 1429 AN: 33334

American (AMR) AF: 0.00880 AC: 390 AN: 44304

Ashkenazi Jewish (ASJ) AF: 0.0472 AC: 1229 AN: 26012

East Asian (EAS) AF: 0.00184 AC: 73 AN: 39622

South Asian (SAS) AF: 0.0301 AC: 2562 AN: 85228

European-Finnish (FIN) AF: 0.0123 AC: 654 AN: 53278

Middle Eastern (MID) AF: 0.0315 AC: 181 AN: 5748

European-Non Finnish (NFE) AF: 0.0168 AC: 18612 AN: 1106064

Other (OTH) AF: 0.0238 AC: 1431 AN: 60140

GnomAD4 genome AF: 0.0235 AC: 3584 AN: 152198 Hom.: 60 Cov.: 31 AF XY: 0.0230 AC XY: 1712 AN XY: 74410

African (AFR) AF: 0.0397 AC: 1650 AN: 41538

American (AMR) AF: 0.0150 AC: 230 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 149 AN: 3468

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5178

South Asian (SAS) AF: 0.0247 AC: 119 AN: 4810

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10606

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0176 AC: 1197 AN: 68004

Other (OTH) AF: 0.0266 AC: 56 AN: 2104

Alfa AF: 0.0215 Hom.: 23

Bravo AF: 0.0236

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.612+8T>C in intron 8 of NEB: This variant is not expected to have clinical sig nificance because it is not located within the conserved splice consensus sequen ce. It has been identified in 3.7% (148/3974) of African American chromosomes fr om a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu/EVS; dbSNP rs113095802). -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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. -

Oct 16, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 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.612+8T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.019 in 272532 control chromosomes in the gnomAD database, including 70 homozygotes. The observed variant frequency is approximately 5 fold of 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.612+8T>C in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 12, 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

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 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. -

not provided Benign:2

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.55
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.066
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: rs113095802; hg19: chr2-152580766;