NM_001164507.2:c.19944+3G>A

Variant names:

• chr2-151551735-C-T
• rs115142419
• NM_001164507.2:c.19944+3G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS1

The NM_001164507.2(NEB):​c.19944+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,612,008 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: NEB NM_001164507.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002263
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.22
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-151551735-C-T is Benign according to our data. Variant chr2-151551735-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 465529.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 = 0.00226 (344/152286) while in subpopulation AFR AF = 0.00739 (307/41570). AF 95% confidence interval is 0.00671. There are 0 homozygotes in GnomAd4. There are 169 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.19944+3G>A		splice_region intron	N/A	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.19944+3G>A		splice_region intron	N/A	NP_001157980.2
	NEB	NM_001271208.2		c.19944+3G>A		splice_region intron	N/A	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.19944+3G>A		splice_region intron	N/A	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.19944+3G>A		splice_region intron	N/A	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.14841+3G>A		splice_region intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 343 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00738

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000572 AC: 142 AN: 248190 AF XY: 0.000520

Gnomad AFR exome AF: 0.00797

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.0000561

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000249 AC: 364 AN: 1459722 Hom.: 0 Cov.: 30 AF XY: 0.000237 AC XY: 172 AN XY: 726294

African (AFR) AF: 0.00766 AC: 256 AN: 33438

American (AMR) AF: 0.000627 AC: 28 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26108

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39598

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5756

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1110366

Other (OTH) AF: 0.000846 AC: 51 AN: 60294

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74464

African (AFR) AF: 0.00739 AC: 307 AN: 41570

American (AMR) AF: 0.00170 AC: 26 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00269

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NEB-related disorder Benign:1

May 20, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided Benign:1

Jan 20, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nemaline myopathy 2 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Benign	0.80
PhyloP100		1.2
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.042
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: rs115142419; hg19: chr2-152408249;