2-151656478-A-T

Variant names:

• chr2-151656478-A-T
• rs10173335
• NM_001164507.2:c.6184-14T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):​c.6184-14T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0602 in 1,568,950 control chromosomes in the GnomAD database, including 4,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1373 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2882 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0720
• 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]

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=-0.81).
• BP6: Variant 2-151656478-A-T is Benign according to our data. Variant chr2-151656478-A-T is described in ClinVar as Benign. ClinVar VariationId is 226846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.6184-14T>A		intron_variant	Intron 48 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.6184-14T>A		intron_variant	Intron 48 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.6184-14T>A		intron_variant	Intron 48 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.6184-14T>A		intron_variant	Intron 48 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.6184-14T>A		intron_variant	Intron 48 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15447 AN: 152022 Hom.: 1370 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0602

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0499

Gnomad SAS AF: 0.0550

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0532

Gnomad OTH AF: 0.0903

GnomAD2 exomes AF: 0.0598 AC: 14166 AN: 236936 AF XY: 0.0576

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.0331

Gnomad ASJ exome AF: 0.0909

Gnomad EAS exome AF: 0.0448

Gnomad FIN exome AF: 0.0148

Gnomad NFE exome AF: 0.0522

Gnomad OTH exome AF: 0.0565

GnomAD4 exome AF: 0.0558 AC: 79013 AN: 1416810 Hom.: 2882 Cov.: 30 AF XY: 0.0552 AC XY: 38661 AN XY: 700956

African (AFR) AF: 0.231 AC: 7497 AN: 32466

American (AMR) AF: 0.0361 AC: 1557 AN: 43158

Ashkenazi Jewish (ASJ) AF: 0.0927 AC: 2284 AN: 24648

East Asian (EAS) AF: 0.0518 AC: 2036 AN: 39286

South Asian (SAS) AF: 0.0528 AC: 4165 AN: 78850

European-Finnish (FIN) AF: 0.0158 AC: 824 AN: 52278

Middle Eastern (MID) AF: 0.0772 AC: 432 AN: 5596

European-Non Finnish (NFE) AF: 0.0521 AC: 56341 AN: 1082062

Other (OTH) AF: 0.0663 AC: 3877 AN: 58466

GnomAD4 genome AF: 0.102 AC: 15470 AN: 152140 Hom.: 1373 Cov.: 32 AF XY: 0.0977 AC XY: 7264 AN XY: 74384

African (AFR) AF: 0.233 AC: 9674 AN: 41460

American (AMR) AF: 0.0600 AC: 916 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 367 AN: 3472

East Asian (EAS) AF: 0.0496 AC: 257 AN: 5182

South Asian (SAS) AF: 0.0545 AC: 263 AN: 4828

European-Finnish (FIN) AF: 0.0122 AC: 130 AN: 10616

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0533 AC: 3622 AN: 68004

Other (OTH) AF: 0.0894 AC: 189 AN: 2114

Alfa AF: 0.0397 Hom.: 41

Bravo AF: 0.111

Asia WGS AF: 0.0840 AC: 294 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Feb 15, 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. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

6184-14T>A in intron 48 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 22.5% (811/3602) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs10173335). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 2 Benign:3

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 27, 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: c.6184-14T>A in NEB gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect the normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at a frequency of 0.06562 (7599 / 115796 chrs tested), including numerous homozygotes across multiple ethnicities. The observed frequency exceed the maximum expected allele frequency for a pathogenic variant of 0.0035. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but cited as Benign by reputable databases/clinical laboratories. Considering all, the variant was classified as Benign. -

Arthrogryposis multiplex congenita 6 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.54
PhyloP100		-0.072
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10173335; hg19: chr2-152512992; COSMIC: COSV51444133;