rs201979610

chr2-151529260-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_001164507.2(NEB):c.21685G>C(p.Asp7229His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,613,710 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (4 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 7.91

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0207026).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00172 (262/152312) while in subpopulation NFE AF= 0.00332 (226/68036). AF 95% confidence interval is 0.00297. There are 0 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.21685G>C	p.Asp7229His	missense_variant	146/182	ENST00000427231.7
NEB	NM_001164508.2	c.21685G>C	p.Asp7229His	missense_variant	146/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.21685G>C	p.Asp7229His	missense_variant	146/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.21685G>C	p.Asp7229His	missense_variant	146/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00183 AC: 456 AN: 249136 Hom.: 1 AF XY: 0.00186 AC XY: 251 AN XY: 135142

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.000835

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.00288 AC: 4205 AN: 1461398 Hom.: 4 Cov.: 30 AF XY: 0.00285 AC XY: 2072 AN XY: 727002

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.000824

Gnomad4 NFE exome AF: 0.00361

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74476

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00332

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00290 Hom.: 0

Bravo AF: 0.00169

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000260 AC: 1

ESP6500EA AF: 0.00277 AC: 23

ExAC AF: 0.00190 AC: 230

EpiCase AF: 0.00229

EpiControl AF: 0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 10, 2015	- -

Nemaline myopathy 2 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 11, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2022	Variant summary: NEB c.21790G>C (p.Asp7264His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 280538 control chromosomes, predominantly at a frequency of 0.0036 within the Non-Finnish European subpopulation in the gnomAD database, including one homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.02 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.21790G>C has been reported in the literature in individuals affected with mild Nemaline Myopathy, sporadic distal myopathy and dilated cardiomyopathy (Wallgren-Pettersson_ 2004, Minoche_2019, Morales_2021). These reports do not provide unequivocal conclusions about association of the variant with Nemaline Myopathy 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed this variant since 2014: two classified the variant as of uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2017	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. -

NEB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2023

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;T;D;D;D;.;.
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.021	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D;D;.;D;D;D;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;D;.;D;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		0.99	.;.;.;.;D;.;.;.
Vest4		0.60
MVP		0.71
MPC		0.36
ClinPred		0.050	T
GERP RS		5.8
Varity_R		0.49
gMVP		0.57

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: rs201979610; hg19: chr2-152385774; COSMIC: COSV50813248; COSMIC: COSV50813248;