rs114218081

Variant names:

• chr2-151533477-A-G
• rs114218081
• NM_001164508.2:c.21382T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.21382T>C​(p.Leu7128Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0215 in 1,551,314 control chromosomes in the GnomAD database, including 436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (66 hom., cov: 33)
  • Exomes 𝑓: 0.021 (370 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.75
• Publications: 4 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-151533477-A-G is Benign according to our data. Variant chr2-151533477-A-G is described in ClinVar as Benign. ClinVar VariationId is 257788.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 = 0.0259 (3943/152358) while in subpopulation AFR AF = 0.0435 (1807/41576). AF 95% confidence interval is 0.0418. There are 66 homozygotes in GnomAd4. There are 1957 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 66 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164508.2	c.21382T>C	p.Leu7128Leu	synonymous_variant	Exon 143 of 182	ENST00000397345.8	NP_001157980.2
NEB	NM_001164507.2	c.21417+738T>C		intron_variant	Intron 143 of 181	ENST00000427231.7	NP_001157979.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.21382T>C	p.Leu7128Leu	synonymous_variant	Exon 143 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.21417+738T>C		intron_variant	Intron 143 of 181	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3932 AN: 152240 Hom.: 66 Cov.: 33

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0248

GnomAD2 exomes AF: 0.0183 AC: 2883 AN: 157248 AF XY: 0.0172

Gnomad AFR exome AF: 0.0411

Gnomad AMR exome AF: 0.00915

Gnomad ASJ exome AF: 0.0227

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0211 AC: 29472 AN: 1398956 Hom.: 370 Cov.: 30 AF XY: 0.0204 AC XY: 14071 AN XY: 690012

African (AFR) AF: 0.0453 AC: 1429 AN: 31568

American (AMR) AF: 0.0103 AC: 368 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 582 AN: 25174

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35724

South Asian (SAS) AF: 0.00713 AC: 565 AN: 79220

European-Finnish (FIN) AF: 0.0351 AC: 1729 AN: 49278

Middle Eastern (MID) AF: 0.0105 AC: 60 AN: 5694

European-Non Finnish (NFE) AF: 0.0219 AC: 23574 AN: 1078566

Other (OTH) AF: 0.0201 AC: 1164 AN: 58032

GnomAD4 genome AF: 0.0259 AC: 3943 AN: 152358 Hom.: 66 Cov.: 33 AF XY: 0.0263 AC XY: 1957 AN XY: 74504

African (AFR) AF: 0.0435 AC: 1807 AN: 41576

American (AMR) AF: 0.0121 AC: 185 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4832

European-Finnish (FIN) AF: 0.0405 AC: 430 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0197 AC: 1337 AN: 68040

Other (OTH) AF: 0.0246 AC: 52 AN: 2116

Alfa AF: 0.0238 Hom.: 33

Bravo AF: 0.0253

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Feb 01, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 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:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

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	-0.42
CADD	Benign	7.6
DANN	Benign	0.82
PhyloP100		3.8
Mutation Taster		=93/7	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: rs114218081; hg19: chr2-152389991;