rs118191309

chr2-151506216-T-G

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.23599A>C(p.Lys7867Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,613,806 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (30 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.90

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004918307).
• BP6: Variant 2-151506216-T-G is Benign according to our data. Variant chr2-151506216-T-G is described in ClinVar as [Benign]. Clinvar id is 194308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151506216-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00225 (343/152370) while in subpopulation EAS AF= 0.0442 (229/5182). AF 95% confidence interval is 0.0395. There are 8 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.23599A>C	p.Lys7867Gln	missense_variant	164/182	ENST00000427231.7
NEB	NM_001164508.2	c.23599A>C	p.Lys7867Gln	missense_variant	164/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.23599A>C	p.Lys7867Gln	missense_variant	164/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.23599A>C	p.Lys7867Gln	missense_variant	164/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152252 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0449

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00526 AC: 1311 AN: 249152 Hom.: 20 AF XY: 0.00484 AC XY: 654 AN XY: 135150

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0473

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00155 AC: 2266 AN: 1461436 Hom.: 30 Cov.: 30 AF XY: 0.00148 AC XY: 1074 AN XY: 727014

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00932

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0307

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000200

Gnomad4 OTH exome AF: 0.00388

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152370 Hom.: 8 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74520

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0442

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000864 Hom.: 1

Bravo AF: 0.00309

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00478 AC: 578

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 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. -

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2017	Variant summary: The NEB c.23704A>C (p.Lys7902Gln) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 4/4 in silico tools. This variant was found in 578/120716 control chromosomes (13 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.045908 (396/8626). This frequency is about 13 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	21
Dann	Benign	0.97
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.73	T;T;T;T;T;T;.;.;D
MetaRNN	Benign	0.0049	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.41	N;.;.;.;N;.;.;.;.
MutationTaster	Benign	0.95	D;D;D;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.36	N;N;.;N;N;N;.;.;N
REVEL	Benign	0.082
Sift	Benign	0.28	T;T;.;T;T;T;.;.;T
Sift4G	Benign	0.20	T;T;T;T;T;T;T;T;.
Polyphen		0.0020	.;.;.;.;B;.;.;.;.
Vest4		0.27
MVP		0.43
MPC		0.075
ClinPred		0.011	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.23

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: rs118191309; hg19: chr2-152362730;