2-151525997-G-C

Variant names:

• chr2-151525997-G-C
• rs192402741
• NM_001164507.2:c.22122C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001164507.2(NEB):​c.22122C>G​(p.Asp7374Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,613,972 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D7374D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (23 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.392
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008312732).
• BP6: Variant 2-151525997-G-C is Benign according to our data. Variant chr2-151525997-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 378269.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0032 (488/152322) while in subpopulation NFE AF = 0.00587 (399/68030). AF 95% confidence interval is 0.00539. There are 3 homozygotes in GnomAd4. There are 215 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.22122C>G	p.Asp7374Glu	missense	Exon 150 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.22122C>G	p.Asp7374Glu	missense	Exon 150 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.22227C>G	p.Asp7409Glu	missense	Exon 151 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.22122C>G	p.Asp7374Glu	missense	Exon 150 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.22122C>G	p.Asp7374Glu	missense	Exon 150 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.17019C>G	p.Asp5673Glu	missense	Exon 123 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 488 AN: 152204 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00586

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00317 AC: 790 AN: 249106 AF XY: 0.00326

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00579

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.00453 AC: 6614 AN: 1461650 Hom.: 23 Cov.: 32 AF XY: 0.00454 AC XY: 3300 AN XY: 727114

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.000872 AC: 39 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00187 AC: 49 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86258

European-Finnish (FIN) AF: 0.00155 AC: 83 AN: 53402

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.00550 AC: 6113 AN: 1111810

Other (OTH) AF: 0.00340 AC: 205 AN: 60374

GnomAD4 genome AF: 0.00320 AC: 488 AN: 152322 Hom.: 3 Cov.: 32 AF XY: 0.00289 AC XY: 215 AN XY: 74486

African (AFR) AF: 0.000818 AC: 34 AN: 41568

American (AMR) AF: 0.000916 AC: 14 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00587 AC: 399 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00541 Hom.: 0

Bravo AF: 0.00292

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000492 AC: 2

ESP6500EA AF: 0.00512 AC: 43

ExAC AF: 0.00340 AC: 411

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00516

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Mar 16, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEB: BS2

Nemaline myopathy 2 Uncertain:1 Benign:1

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.

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Oct 03, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 24, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEB-related disorder Benign:1

Apr 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.39
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.072
Sift	Benign	0.55	T
Sift4G	Benign	0.24	T
Polyphen		0.090	B
Vest4		0.49
MutPred		0.38		Gain of loop (P = 0.0502)
MVP		0.34
MPC		0.085
ClinPred		0.0096	T
GERP RS		-0.81
Varity_R		0.084
gMVP		0.26
Mutation Taster		=97/3	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: rs192402741; hg19: chr2-152382511; COSMIC: COSV51453511; COSMIC: COSV51453511;