chr2-151546334-T-C

Variant names:

• chr2-151546334-T-C
• rs181826071
• NM_001164507.2:c.20466+11A>G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BS1 BS2_Supporting

The NM_001164508.2(NEB):​c.20466+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,606,068 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (5 hom.)
• Consequence: NEB NM_001164508.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.763

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]

LOC124906081 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-151546334-T-C is Benign according to our data. Variant chr2-151546334-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257785.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00196 (298/152280) while in subpopulation NFE AF= 0.00293 (199/68018). AF 95% confidence interval is 0.00259. There are 1 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.20466+11A>G		intron_variant	Intron 134 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.20466+11A>G		intron_variant	Intron 134 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.20466+11A>G		intron_variant	Intron 134 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.20466+11A>G		intron_variant	Intron 134 of 181	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 298 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00575

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00179 AC: 439 AN: 245096 Hom.: 0 AF XY: 0.00189 AC XY: 251 AN XY: 132874

Gnomad AFR exome AF: 0.000648

Gnomad AMR exome AF: 0.000354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00514

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.00219

GnomAD4 exome AF: 0.00220 AC: 3201 AN: 1453788 Hom.: 5 Cov.: 30 AF XY: 0.00210 AC XY: 1521 AN XY: 723222

Gnomad4 AFR exome AF: 0.000421

Gnomad4 AMR exome AF: 0.000431

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00529

Gnomad4 NFE exome AF: 0.00253

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00196 AC: 298 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74452

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00575

Gnomad4 NFE AF: 0.00293

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.00125

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:1

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: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.85
CADD	Benign	0.081
DANN	Benign	0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs181826071; hg19: chr2-152402848;