rs61730765

Positions:

• chr2-151526245-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001164507.2(NEB):​c.21963A>G​(p.Lys7321=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,611,434 control chromosomes in the GnomAD database, including 501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (89 hom., cov: 32)
  • Exomes 𝑓: 0.021 (412 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.394

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-151526245-T-C is Benign according to our data. Variant chr2-151526245-T-C is described in ClinVar as [Benign]. Clinvar id is 129729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151526245-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.394 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.21963A>G	p.Lys7321=	synonymous_variant	149/182	ENST00000427231.7
NEB	NM_001164508.2	c.21963A>G	p.Lys7321=	synonymous_variant	149/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.21963A>G	p.Lys7321=	synonymous_variant	149/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.21963A>G	p.Lys7321=	synonymous_variant	149/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4406 AN: 152116 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0202 AC: 4926 AN: 244162 Hom.: 80 AF XY: 0.0191 AC XY: 2532 AN XY: 132338

Gnomad AFR exome AF: 0.0540

Gnomad AMR exome AF: 0.00928

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00659

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0214 AC: 31194 AN: 1459200 Hom.: 412 Cov.: 32 AF XY: 0.0206 AC XY: 14967 AN XY: 725660

Gnomad4 AFR exome AF: 0.0590

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0230

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00702

Gnomad4 FIN exome AF: 0.0352

Gnomad4 NFE exome AF: 0.0219

Gnomad4 OTH exome AF: 0.0209

GnomAD4 genome AF: 0.0290 AC: 4419 AN: 152234 Hom.: 89 Cov.: 32 AF XY: 0.0295 AC XY: 2193 AN XY: 74442

Gnomad4 AFR AF: 0.0544

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0245 Hom.: 36

Bravo AF: 0.0291

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Nemaline myopathy 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.2
DANN	Benign	0.50

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: rs61730765; hg19: chr2-152382759;