rs201714437

chr2-151485875-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164507.2(NEB):c.25463A>G(p.Lys8488Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000739 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. K8488K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 1.48

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11267087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.25463A>G	p.Lys8488Arg	missense_variant	182/182	ENST00000427231.7
NEB	NM_001164508.2	c.25463A>G	p.Lys8488Arg	missense_variant	182/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.25463A>G	p.Lys8488Arg	missense_variant	182/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.25463A>G	p.Lys8488Arg	missense_variant	182/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000313 AC: 78 AN: 248884 Hom.: 0 AF XY: 0.000296 AC XY: 40 AN XY: 135010

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000674

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000783 AC: 1144 AN: 1461664 Hom.: 0 Cov.: 31 AF XY: 0.000752 AC XY: 547 AN XY: 727114

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00100

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74386

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000731 Hom.: 0

Bravo AF: 0.000359

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000497 AC: 2

ESP6500EA AF: 0.000714 AC: 6

ExAC AF: 0.000281 AC: 34

EpiCase AF: 0.000927

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Nemaline myopathy 2 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 30, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 11, 2018	Variant summary: NEB c.25568A>G (p.Lys8523Arg) results in a conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 120734 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.00028 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.25568A>G in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 21, 2016	- -

NEB-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2023

The NEB c.25568A>G variant is predicted to result in the amino acid substitution p.Lys8523Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.064% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-152342389-T-C). In ClinVar, this variant has been classified as uncertain and likely benign by several clinical labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/435961/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.19895A>G (p.K6632R) alteration is located in exon 150 (coding exon 148) of the NEB gene. This alteration results from a A to G substitution at nucleotide position 19895, causing the lysine (K) at amino acid position 6632 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	15
Dann	Benign	0.95
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.71	T;T;T;T;T;T;.;.
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.17	N;.;.;.;N;.;.;.
MutationTaster	Benign	0.50	D;D;D;D;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N;N;.;N;N;N;.;.
REVEL	Benign	0.17
Sift	Benign	0.28	T;T;.;T;T;T;.;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T
Polyphen		0.0060	.;.;.;.;B;.;.;.
Vest4		0.096
MVP		0.48
MPC		0.047
ClinPred		0.045	T
GERP RS		2.9
Varity_R		0.091
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs201714437; hg19: chr2-152342389;