rs193224180

chr2-151503408-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001164507.2(NEB):c.23776C>T(p.Pro7926Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00181 in 1,612,560 control chromosomes in the GnomAD database, including 6 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 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 3.94

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: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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021578938).
• BP6: Variant 2-151503408-G-A is Benign according to our data. Variant chr2-151503408-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194312.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00135 (205/152262) while in subpopulation NFE AF= 0.00256 (174/68010). AF 95% confidence interval is 0.00225. There are 0 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.23776C>T	p.Pro7926Ser	missense_variant	166/182	ENST00000427231.7
NEB	NM_001164508.2	c.23776C>T	p.Pro7926Ser	missense_variant	166/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.23776C>T	p.Pro7926Ser	missense_variant	166/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.23776C>T	p.Pro7926Ser	missense_variant	166/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00110 AC: 274 AN: 248950 Hom.: 0 AF XY: 0.00107 AC XY: 144 AN XY: 135078

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.00186 AC: 2719 AN: 1460298 Hom.: 6 Cov.: 29 AF XY: 0.00173 AC XY: 1260 AN XY: 726472

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00228

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74446

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00256

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00200 Hom.: 0

Bravo AF: 0.00128

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000546 AC: 2

ESP6500EA AF: 0.00293 AC: 24

ExAC AF: 0.000952 AC: 115

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NEB p.Pro7926Ser variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs193224180), ClinVar (classified as likely benign by EGL Genetics and as a VUS by Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine and Invitae for nemaline myopathy 2) and LOVD 3.0. The variant was identified in control databases in 316 of 280356 chromosomes at a frequency of 0.001127 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 260 of 128302 chromosomes (freq: 0.002026), Latino in 38 of 35298 chromosomes (freq: 0.001077), Other in 6 of 7122 chromosomes (freq: 0.000843), African in 8 of 24192 chromosomes (freq: 0.000331), European (Finnish) in 3 of 25010 chromosomes (freq: 0.00012) and Ashkenazi Jewish in 1 of 10348 chromosomes (freq: 0.000097); it was not observed in the East Asian and South Asian populations. The p.Pro7926 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2023	Reported previously in a child with congenital cataracts, ptosis, hypotonia, delay in motor skills, dysphagia, and respiratory failure, who has variants in multiple other genes (Marcos et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32420686) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	NEB: PM2:Supporting, PM3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 06, 2021	- -

Nemaline myopathy 2 Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Pro7961Ser va riant in NEB has not been previously reported in individuals with myopathy, but has been identified in 0.15% (97/66646) of European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs193224180). C omputational prediction tools and conservation analysis do not provide strong su pport for or against an impact to the protein. In summary, while the clinical si gnificance of the p.Pro7961Ser variant is uncertain, these data suggest that it is more likely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2015	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2022

The c.18673C>T (p.P6225S) alteration is located in exon 139 (coding exon 137) of the NEB gene. This alteration results from a C to T substitution at nucleotide position 18673, causing the proline (P) at amino acid position 6225 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T;D;D;D;T;T;.;.;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.2	M;.;.;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D;N;.;D;D;D;.;.;D
REVEL	Benign	0.13
Sift	Benign	0.32	T;T;.;T;T;T;.;.;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D;D;.
Polyphen		0.20	.;.;.;.;B;.;.;.;.
Vest4		0.63
MVP		0.38
MPC		0.33
ClinPred		0.051	T
GERP RS		5.4
Varity_R		0.21
gMVP		0.31

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: rs193224180; hg19: chr2-152359922;