2-151485949-GA-GAA

Variant names:

• chr2-151485949-G-GA
• rs148839798
• NM_001164507.2:c.25405-17dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.25405-17dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,612,194 control chromosomes in the GnomAD database, including 41 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (32 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.683
• 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]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-151485949-G-GA is Benign according to our data. Variant chr2-151485949-G-GA is described in ClinVar as Benign. ClinVar VariationId is 257805.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 = 0.00233 (355/152298) while in subpopulation EAS AF = 0.0455 (236/5186). AF 95% confidence interval is 0.0407. There are 9 homozygotes in GnomAd4. There are 186 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.25405-17dupT		intron_variant	Intron 181 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.25405-17dupT		intron_variant	Intron 181 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.25405-17_25405-16insT		intron_variant	Intron 181 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.25405-17_25405-16insT		intron_variant	Intron 181 of 181	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 357 AN: 152180 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0462

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00540 AC: 1332 AN: 246826 AF XY: 0.00502

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0483

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000341

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00159 AC: 2316 AN: 1459896 Hom.: 32 Cov.: 30 AF XY: 0.00152 AC XY: 1104 AN XY: 726314

African (AFR) AF: 0.000389 AC: 13 AN: 33454

American (AMR) AF: 0.00946 AC: 423 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0310 AC: 1231 AN: 39666

South Asian (SAS) AF: 0.00189 AC: 163 AN: 86214

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52732

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000221 AC: 246 AN: 1110932

Other (OTH) AF: 0.00393 AC: 237 AN: 60316

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152298 Hom.: 9 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74468

African (AFR) AF: 0.000577 AC: 24 AN: 41560

American (AMR) AF: 0.00379 AC: 58 AN: 15286

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

East Asian (EAS) AF: 0.0455 AC: 236 AN: 5186

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68030

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00142 Hom.: 1

Bravo AF: 0.00314

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 08, 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.

not provided Benign:1

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.25510-17dupT variant involves the duplication of an intronic nucleotide 17 basepairs away from the exon-intron junction. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts no significant impact on ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC in 585 of 119984 control chromosomes (13 homozygotes) in all ethnicities, but was predominantly observed in the East Asian subpopulation at a frequency of 0.046692 (398/8524 [11 homozygotes]). This frequency is about 13 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), providing strong evidence that this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, one clinical diagnostic laboratory has classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.

Nemaline myopathy 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.68
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: rs148839798; hg19: chr2-152342463;