rs201825451

Positions:

• chr2-151492120-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001164507.2(NEB):​c.25035C>T​(p.Asp8345=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,808 control chromosomes in the GnomAD database, including 9 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 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.954

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-151492120-G-A is Benign according to our data. Variant chr2-151492120-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95123.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=1}.
• BP7: Synonymous conserved (PhyloP=0.954 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00111 (1627/1461662) while in subpopulation MID AF= 0.00972 (56/5762). AF 95% confidence interval is 0.00768. There are 8 homozygotes in gnomad4_exome. There are 844 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.25035C>T	p.Asp8345=	synonymous_variant	178/182	ENST00000427231.7
NEB	NM_001164508.2	c.25035C>T	p.Asp8345=	synonymous_variant	178/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.25035C>T	p.Asp8345=	synonymous_variant	178/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.25035C>T	p.Asp8345=	synonymous_variant	178/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152028 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00157 AC: 391 AN: 249120 Hom.: 4 AF XY: 0.00168 AC XY: 227 AN XY: 135146

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00111 AC: 1627 AN: 1461662 Hom.: 8 Cov.: 31 AF XY: 0.00116 AC XY: 844 AN XY: 727110

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000718

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152146 Hom.: 1 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74382

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00232 Hom.: 3

Bravo AF: 0.00140

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2018	This variant is associated with the following publications: (PMID: 25203624) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	NEB: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2016	- -

Nemaline myopathy 2 Uncertain:1 Benign:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.9
DANN	Benign	0.81

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: rs201825451; hg19: chr2-152348634;