NM_001164507.2:c.21856G>A

Variant names:

• chr2-151527007-C-T
• rs35625617
• NM_001164507.2:c.21856G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.21856G>A​(p.Asp7286Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,595,150 control chromosomes in the GnomAD database, including 475 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (34 hom., cov: 32)
  • Exomes 𝑓: 0.022 (441 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 7.62
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062577724).
• BP6: Variant 2-151527007-C-T is Benign according to our data. Variant chr2-151527007-C-T is described in ClinVar as Benign. ClinVar VariationId is 129728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0163 (2484/152210) while in subpopulation NFE AF = 0.0231 (1571/68000). AF 95% confidence interval is 0.0222. There are 34 homozygotes in GnomAd4. There are 1276 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.21856G>A	p.Asp7286Asn	missense_variant	Exon 148 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.21856G>A	p.Asp7286Asn	missense_variant	Exon 148 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.21856G>A	p.Asp7286Asn	missense_variant	Exon 148 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.21856G>A	p.Asp7286Asn	missense_variant	Exon 148 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2484 AN: 152092 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.0533

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.0164 AC: 3637 AN: 221556 AF XY: 0.0168

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.00148

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0507

Gnomad NFE exome AF: 0.0226

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0221 AC: 31950 AN: 1442940 Hom.: 441 Cov.: 30 AF XY: 0.0217 AC XY: 15531 AN XY: 715878

African (AFR) AF: 0.00391 AC: 130 AN: 33280

American (AMR) AF: 0.00510 AC: 218 AN: 42754

Ashkenazi Jewish (ASJ) AF: 0.00210 AC: 54 AN: 25718

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39250

South Asian (SAS) AF: 0.00407 AC: 339 AN: 83292

European-Finnish (FIN) AF: 0.0497 AC: 2604 AN: 52438

Middle Eastern (MID) AF: 0.00348 AC: 20 AN: 5748

European-Non Finnish (NFE) AF: 0.0250 AC: 27539 AN: 1100832

Other (OTH) AF: 0.0175 AC: 1045 AN: 59628

GnomAD4 genome AF: 0.0163 AC: 2484 AN: 152210 Hom.: 34 Cov.: 32 AF XY: 0.0171 AC XY: 1276 AN XY: 74414

African (AFR) AF: 0.00494 AC: 205 AN: 41540

American (AMR) AF: 0.00621 AC: 95 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4814

European-Finnish (FIN) AF: 0.0533 AC: 565 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0231 AC: 1571 AN: 68000

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.0195 Hom.: 130

Bravo AF: 0.0126

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.00367 AC: 14

ESP6500EA AF: 0.0238 AC: 196

ExAC AF: 0.0144 AC: 1736

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp7321Asn in exon 149 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 2.4% (196/8230) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs35625617). -

Jan 27, 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. -

Feb 09, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NEB c.21961G>A (p.Asp7321Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.016 in 221556 control chromosomes in the gnomAD database, including 40 homozygotes. The observed variant frequency is approximately 4.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NEB causing Nemaline Myopathy 2 phenotype (0.0035), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.21961G>A in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=4)/likely benign(n=1). Based on the evidence outlined above, the variant was classified as benign. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nemaline myopathy 2 Benign:3

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

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	.;.;T;.;T;T;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;T;D;D;D;.;.
MetaRNN	Benign	0.0063	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M;.;.;.
PhyloP100		7.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N;D;.;D;N;D;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0090	D;D;.;D;D;D;.;.
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.;.
Vest4		0.54
MPC		0.34
ClinPred		0.038	T
GERP RS		6.0
Varity_R		0.28
gMVP		0.75
Mutation Taster		=99/1	polymorphism (auto)

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: rs35625617; hg19: chr2-152383521; COSMIC: COSV107246877; COSMIC: COSV107246877;