2-151604849-C-T

Position:

• chr2-151604849-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001164507.2(NEB):​c.12770G>A​(p.Arg4257His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 8)
  • Exomes 𝑓: 0.00043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.25

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009276062).
• BP6: Variant 2-151604849-C-T is Benign according to our data. Variant chr2-151604849-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 509194.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.12770G>A	p.Arg4257His	missense_variant	85/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.12770G>A	p.Arg4257His	missense_variant	85/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.12770G>A	p.Arg4257His	missense_variant	85/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.12770G>A	p.Arg4257His	missense_variant	85/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.11601+4960G>A		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.00 AC: 170 AN: 61412 Hom.: 1 Cov.: 8 FAILED QC

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00280

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00714

Gnomad NFE AF: 0.0000582

Gnomad OTH AF: 0.00407

GnomAD3 exomes AF: 0.00147 AC: 74 AN: 50432 Hom.: 0 AF XY: 0.00102 AC XY: 26 AN XY: 25390

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.000445

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000140

Gnomad SAS exome AF: 0.000169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.00115

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000433 AC: 192 AN: 443338 Hom.: 0 Cov.: 5 AF XY: 0.000347 AC XY: 81 AN XY: 233412

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000452

Gnomad4 SAS exome AF: 0.0000917

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000515

Gnomad4 OTH exome AF: 0.00120

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00277 AC: 170 AN: 61474 Hom.: 1 Cov.: 8 AF XY: 0.00244 AC XY: 70 AN XY: 28658

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.00279

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000582

Gnomad4 OTH AF: 0.00402

ExAC AF: 0.00104 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 04, 2017	This variant occurs in a region of NEB (Exons 82-105) consisting of three highly homologous 8-exon repeat units (exons 82-89, exons 90-97, exons 98-105). Sequence variants in this region can be detected, but this assay cannot determine which of the three repeat units is affected, and zygosity is often ambiguous. All variants in this region are reported relative to the exon 82-89 repeat. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with NEB-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Benign	0.86
DEOGEN2	Benign	0.029	.;T;.;.;.
Eigen	Benign	0.010
Eigen_PC	Benign	-0.00082
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D;D;.;.
MetaRNN	Benign	0.0093	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	0.91	D;D;D;D
PROVEAN	Benign	-1.1	N;.;N;.;.
REVEL	Benign	0.12
Sift	Benign	0.055	T;.;T;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Vest4		0.36
MutPred		0.50		Loss of MoRF binding (P = 0.0232);Loss of MoRF binding (P = 0.0232);Loss of MoRF binding (P = 0.0232);Loss of MoRF binding (P = 0.0232);Loss of MoRF binding (P = 0.0232);
MVP		0.69
MPC		0.34
ClinPred		0.043	T
GERP RS		3.2
gMVP		0.0023

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: rs576918934; hg19: chr2-152461363;