2-151485949-GA-GAA

Position:

chr2-151485949-GA-GAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001164508.2(NEB):c.25405-17dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,612,194 control chromosomes in the GnomAD database, including 41 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 32 hom. )

Consequence

NEB
NM_001164508.2 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.683

Variant links:

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]

NEB links:

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]

RIF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 2-151485949-G-GA is Benign according to our data. Variant chr2-151485949-G-GA is described in ClinVar as [Benign]. Clinvar id is 257805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00233 (355/152298) while in subpopulation EAS AF= 0.0455 (236/5186). AF 95% confidence interval is 0.0407. There are 9 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.25405-17dupT		intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.25405-17dupT		intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.25405-17_25405-16insT		intron_variant		5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.25405-17_25405-16insT		intron_variant		5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

357

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0462

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00540

AC:

1332

AN:

246826

Hom.:

AF XY:

0.00502

AC XY:

673

AN XY:

134062

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0483

Gnomad SAS exome

AF:

0.00190

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000341

Gnomad OTH exome

AF:

0.00299

GnomAD4 exome

AF:

0.00159

AC:

2316

AN:

1459896

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

1104

AN XY:

726314

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.00946

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0310

Gnomad4 SAS exome

AF:

0.00189

Gnomad4 FIN exome

AF:

0.0000379

Gnomad4 NFE exome

AF:

0.000221

Gnomad4 OTH exome

AF:

0.00393

GnomAD4 genome

AF:

0.00233

AC:

355

AN:

152298

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0455

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00142

Hom.:

Bravo

AF:

0.00314

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 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	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 24, 2017

Variant summary: The NEB c.25510-17dupT variant involves the duplication of an intronic nucleotide 17 basepairs away from the exon-intron junction. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts no significant impact on ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC in 585 of 119984 control chromosomes (13 homozygotes) in all ethnicities, but was predominantly observed in the East Asian subpopulation at a frequency of 0.046692 (398/8524 [11 homozygotes]). This frequency is about 13 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), providing strong evidence that this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, one clinical diagnostic laboratory has classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Nemaline myopathy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over