rs35625617

chr2-151527007-C-T

Variant summary

Our verdict is Benign. Variant got -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:11
• Conservation: PhyloP100: 7.62

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:):

ACMG classification

Verdict is Benign. Variant got -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 id is 129728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151527007-C-T is described in Lovd as [Benign]. Variant chr2-151527007-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.21856G>A	p.Asp7286Asn	missense_variant	148/182	ENST00000427231.7
NEB	NM_001164508.2	c.21856G>A	p.Asp7286Asn	missense_variant	148/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.21856G>A	p.Asp7286Asn	missense_variant	148/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.21856G>A	p.Asp7286Asn	missense_variant	148/182	5	NM_001164507.2	A2

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

GnomAD3 exomes AF: 0.0164 AC: 3637 AN: 221556 Hom.: 40 AF XY: 0.0168 AC XY: 2000 AN XY: 119054

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 SAS exome AF: 0.00395

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

Gnomad4 AFR exome AF: 0.00391

Gnomad4 AMR exome AF: 0.00510

Gnomad4 ASJ exome AF: 0.00210

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00407

Gnomad4 FIN exome AF: 0.0497

Gnomad4 NFE exome AF: 0.0250

Gnomad4 OTH exome AF: 0.0175

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

Gnomad4 AFR AF: 0.00494

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.0533

Gnomad4 NFE AF: 0.0231

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.0201 Hom.: 59

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 09, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	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). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2020	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -

Nemaline myopathy 2 Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

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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
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;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
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

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: rs35625617; hg19: chr2-152383521;