rs200963111

chr2-151513680-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001164507.2(NEB):c.23141G>A(p.Arg7714Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,599,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 2.39

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01810959).
• BP6: Variant 2-151513680-C-T is Benign according to our data. Variant chr2-151513680-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257796.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.23141G>A	p.Arg7714Gln	missense_variant	160/182	ENST00000427231.7
NEB	NM_001164508.2	c.23141G>A	p.Arg7714Gln	missense_variant	160/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.23141G>A	p.Arg7714Gln	missense_variant	160/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.23141G>A	p.Arg7714Gln	missense_variant	160/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.000619 AC: 94 AN: 151804 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000142 AC: 32 AN: 225430 Hom.: 0 AF XY: 0.0000906 AC XY: 11 AN XY: 121386

Gnomad AFR exome AF: 0.00184

Gnomad AMR exome AF: 0.0000622

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000242

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000801 AC: 116 AN: 1447796 Hom.: 0 Cov.: 30 AF XY: 0.0000584 AC XY: 42 AN XY: 718666

Gnomad4 AFR exome AF: 0.00249

Gnomad4 AMR exome AF: 0.0000232

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000154

Gnomad4 OTH exome AF: 0.000134

GnomAD4 genome AF: 0.000632 AC: 96 AN: 151920 Hom.: 0 Cov.: 32 AF XY: 0.000539 AC XY: 40 AN XY: 74218

Gnomad4 AFR AF: 0.00225

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.000688

ESP6500AA AF: 0.00160 AC: 6

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000174 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	NEB: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 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:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2023	Variant summary: NEB c.23246G>A (p.Arg7749Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 256704 control chromosomes, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database. This frequency is somewhat lower than estimated maximum for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.0035), allowing no clear conclusions about variant significance. To our knowledge, no occurrence of c.23246G>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, and the variant as uncertain significance (n = 3) or likely benign (n = 2). Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2022

The c.18038G>A (p.R6013Q) alteration is located in exon 133 (coding exon 131) of the NEB gene. This alteration results from a G to A substitution at nucleotide position 18038, causing the arginine (R) at amino acid position 6013 to be replaced by a glutamine (Q). 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	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.82	T;D;T;D;T;D;.;.
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.018	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;.;.;.;L;.;.;.
MutationTaster	Benign	0.94	N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N;N;.;N;N;N;.;.
REVEL	Benign	0.094
Sift	Benign	0.18	T;T;.;T;T;T;.;.
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D
Polyphen		0.99	.;.;.;.;D;.;.;.
Vest4		0.29
MVP		0.56
MPC		0.26
ClinPred		0.069	T
GERP RS		4.5
Varity_R		0.11
gMVP		0.052

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: rs200963111; hg19: chr2-152370194; COSMIC: COSV51436913; COSMIC: COSV51436913;