rs114218081

Positions:

• chr2-151533477-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001164508.2(NEB):​c.21382T>C​(p.Leu7128=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0215 in 1,551,314 control chromosomes in the GnomAD database, including 436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (66 hom., cov: 33)
  • Exomes 𝑓: 0.021 (370 hom.)
• Consequence: NEB NM_001164508.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.75

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-151533477-A-G is Benign according to our data. Variant chr2-151533477-A-G is described in ClinVar as [Benign]. Clinvar id is 257788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151533477-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0259 (3943/152358) while in subpopulation AFR AF= 0.0435 (1807/41576). AF 95% confidence interval is 0.0418. There are 66 homozygotes in gnomad4. There are 1957 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164508.2	c.21382T>C	p.Leu7128=	synonymous_variant	143/182	ENST00000397345.8	NP_001157980.2
NEB	NM_001164507.2	c.21417+738T>C		intron_variant		ENST00000427231.7	NP_001157979.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.21382T>C	p.Leu7128=	synonymous_variant	143/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.21417+738T>C		intron_variant		5	NM_001164507.2	ENSP00000416578	A2

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3932 AN: 152240 Hom.: 66 Cov.: 33

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0248

GnomAD3 exomes AF: 0.0183 AC: 2883 AN: 157248 Hom.: 41 AF XY: 0.0172 AC XY: 1433 AN XY: 83098

Gnomad AFR exome AF: 0.0411

Gnomad AMR exome AF: 0.00915

Gnomad ASJ exome AF: 0.0227

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00667

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0211 AC: 29472 AN: 1398956 Hom.: 370 Cov.: 30 AF XY: 0.0204 AC XY: 14071 AN XY: 690012

Gnomad4 AFR exome AF: 0.0453

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0231

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00713

Gnomad4 FIN exome AF: 0.0351

Gnomad4 NFE exome AF: 0.0219

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome AF: 0.0259 AC: 3943 AN: 152358 Hom.: 66 Cov.: 33 AF XY: 0.0263 AC XY: 1957 AN XY: 74504

Gnomad4 AFR AF: 0.0435

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.0405

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0243 Hom.: 27

Bravo AF: 0.0253

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2022	- -

Nemaline myopathy 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.6
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs114218081; hg19: chr2-152389991;