rs114959904

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001164508.2(NEB):c.2640C>T(p.Arg880Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000793 in 1,596,906 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 3 hom. )

Consequence

NEB
NM_001164508.2 splice_region, synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0890

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 2-151684973-G-A is Benign according to our data. Variant chr2-151684973-G-A is described in ClinVar as [Benign]. Clinvar id is 129737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.089 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00402 (612/152230) while in subpopulation AFR AF= 0.014 (583/41530). AF 95% confidence interval is 0.0131. There are 4 homozygotes in gnomad4. There are 287 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.2640C>T	p.Arg880Arg	splice_region_variant, synonymous_variant	28/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.2640C>T	p.Arg880Arg	splice_region_variant, synonymous_variant	28/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.2640C>T	p.Arg880Arg	splice_region_variant, synonymous_variant	28/182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.2640C>T	p.Arg880Arg	splice_region_variant, synonymous_variant	28/182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.2640C>T	p.Arg880Arg	splice_region_variant, synonymous_variant	28/150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00403

AC:

613

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000927

AC:

207

AN:

223304

Hom.:

AF XY:

0.000833

AC XY:

100

AN XY:

120096

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.000414

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000733

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000161

Gnomad OTH exome

AF:

0.000180

GnomAD4 exome

AF:

0.000453

AC:

654

AN:

1444676

Hom.:

Cov.:

AF XY:

0.000367

AC XY:

263

AN XY:

717024

show subpopulations

Gnomad4 AFR exome

AF:

0.0133

Gnomad4 AMR exome

AF:

0.000424

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000254

Gnomad4 SAS exome

AF:

0.0000599

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000105

Gnomad4 OTH exome

AF:

0.000935

GnomAD4 genome

AF:

0.00402

AC:

612

AN:

152230

Hom.:

Cov.:

AF XY:

0.00386

AC XY:

287

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0140

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00157

Hom.:

Bravo

AF:

0.00445

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	NEB: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 11, 2018	- -

Nemaline myopathy 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 05, 2019	- -

not specified

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

4.9

DANN

Benign

0.85

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