rs34718443

Positions:

• chr2-151529225-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001164507.2(NEB):​c.21720C>T​(p.Tyr7240=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0019 in 1,611,584 control chromosomes in the GnomAD database, including 30 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 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (28 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 4.37

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-151529225-G-A is Benign according to our data. Variant chr2-151529225-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129726.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=6, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00177 (269/152354) while in subpopulation SAS AF= 0.00456 (22/4826). AF 95% confidence interval is 0.00309. There are 2 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.21720C>T	p.Tyr7240=	synonymous_variant	146/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.21720C>T	p.Tyr7240=	synonymous_variant	146/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.21720C>T	p.Tyr7240=	synonymous_variant	146/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.21720C>T	p.Tyr7240=	synonymous_variant	146/182	5	NM_001164507.2	ENSP00000416578	A2

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00268 AC: 668 AN: 249044 Hom.: 7 AF XY: 0.00281 AC XY: 379 AN XY: 135092

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.0300

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00389

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00192 AC: 2801 AN: 1459230 Hom.: 28 Cov.: 30 AF XY: 0.00205 AC XY: 1490 AN XY: 726052

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.0303

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00498

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74512

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00340 Hom.: 1

Bravo AF: 0.00186

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 23, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 15, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2019	This variant is associated with the following publications: (PMID: 25203624) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NEB: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	4.2
DANN	Benign	0.66

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: rs34718443; hg19: chr2-152385739;