rs4664475

chr2-151531039-T-Cchr2-151531039-T-G

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.21585A>G(p.Thr7195=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,611,460 control chromosomes in the GnomAD database, including 297,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24444 hom., cov: 31)
  • Exomes 𝑓: 0.61 (273354 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.29

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=-0.86).
• BP6: Variant 2-151531039-T-C is Benign according to our data. Variant chr2-151531039-T-C is described in ClinVar as [Benign]. Clinvar id is 95114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151531039-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.21585A>G	p.Thr7195=	synonymous_variant	145/182	ENST00000427231.7
NEB	NM_001164508.2	c.21585A>G	p.Thr7195=	synonymous_variant	145/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.21585A>G	p.Thr7195=	synonymous_variant	145/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.21585A>G	p.Thr7195=	synonymous_variant	145/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.555 AC: 84284 AN: 151820 Hom.: 24422 Cov.: 31

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.565

GnomAD3 exomes AF: 0.589 AC: 145970 AN: 247906 Hom.: 44307 AF XY: 0.579 AC XY: 77812 AN XY: 134422

Gnomad AFR exome AF: 0.389

Gnomad AMR exome AF: 0.724

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.578

Gnomad SAS exome AF: 0.409

Gnomad FIN exome AF: 0.639

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.608 AC: 886922 AN: 1459522 Hom.: 273354 Cov.: 39 AF XY: 0.601 AC XY: 436676 AN XY: 726030

Gnomad4 AFR exome AF: 0.387

Gnomad4 AMR exome AF: 0.716

Gnomad4 ASJ exome AF: 0.520

Gnomad4 EAS exome AF: 0.626

Gnomad4 SAS exome AF: 0.410

Gnomad4 FIN exome AF: 0.641

Gnomad4 NFE exome AF: 0.626

Gnomad4 OTH exome AF: 0.590

GnomAD4 genome AF: 0.555 AC: 84339 AN: 151938 Hom.: 24444 Cov.: 31 AF XY: 0.557 AC XY: 41374 AN XY: 74264

Gnomad4 AFR AF: 0.390

Gnomad4 AMR AF: 0.682

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.582

Gnomad4 SAS AF: 0.404

Gnomad4 FIN AF: 0.644

Gnomad4 NFE AF: 0.625

Gnomad4 OTH AF: 0.558

Alfa AF: 0.604 Hom.: 35137

Bravo AF: 0.556

Asia WGS AF: 0.451 AC: 1572 AN: 3478

EpiCase AF: 0.602

EpiControl AF: 0.612

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 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 26, 2014	This is a RefSeq error. The reference base (c.21690A) is the minor allele. This allele (A) has been identified in 38% (3158/8354) of European American chromosom es and 59% (2374/4046) of African American chromosomes by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs4664475) and thus meets criteria to be classified as benign. -
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:4

Benign, 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 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2017	Variant summary: The NEB c.21690A>G (p.Thr7230Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 69172/118646 control chromosomes (20606 homozygotes) at a frequency of 0.5830116, which is approximately 165 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), evidence that this variant is a benign polymorphism. Multiple clinical diagnostic laboratories cite the variant as "benign." Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2019	- -

Arthrogryposis multiplex congenita 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.094
Dann	Benign	0.53

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: rs4664475; hg19: chr2-152387553; COSMIC: COSV51424628; COSMIC: COSV51424628;