rs113048349

Positions:

• chr2-151497725-G-A
• chr2-151497725-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.24208-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,567,582 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (134 hom.)
• Consequence: NEB NM_001164508.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003053
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.516

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:):

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 (BayesDel_noAF=-0.93).
• BP6: Variant 2-151497725-G-A is Benign according to our data. Variant chr2-151497725-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151497725-G-A is described in Lovd as [Benign]. Variant chr2-151497725-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00891 (1356/152222) while in subpopulation NFE AF= 0.0121 (820/68014). AF 95% confidence interval is 0.0114. There are 7 homozygotes in gnomad4. There are 663 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.24208-7C>T		splice_region_variant, intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.24208-7C>T		splice_region_variant, intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.24208-7C>T		splice_region_variant, intron_variant		5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.24208-7C>T		splice_region_variant, intron_variant		5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.00890 AC: 1354 AN: 152104 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.0106 AC: 1899 AN: 179642 Hom.: 20 AF XY: 0.0110 AC XY: 1045 AN XY: 94938

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00317

Gnomad ASJ exome AF: 0.0432

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0116

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0118 AC: 16686 AN: 1415360 Hom.: 134 Cov.: 32 AF XY: 0.0118 AC XY: 8244 AN XY: 699410

Gnomad4 AFR exome AF: 0.00163

Gnomad4 AMR exome AF: 0.00391

Gnomad4 ASJ exome AF: 0.0435

Gnomad4 EAS exome AF: 0.0000263

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.0120

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome AF: 0.00891 AC: 1356 AN: 152222 Hom.: 7 Cov.: 32 AF XY: 0.00891 AC XY: 663 AN XY: 74430

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.0386

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00892

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.0106 Hom.: 3

Bravo AF: 0.00812

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	24313-7C>T in intron 171 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 1.3% (42/3182) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs113048349). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	NEB: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Nemaline myopathy 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.41
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0020
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: rs113048349; hg19: chr2-152354239;