2-151675340-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001164507.2(NEB):c.3826C>A(p.Pro1276Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 1,594,702 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1276R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (1 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.35

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010675073).
• BP6: Variant 2-151675340-G-T is Benign according to our data. Variant chr2-151675340-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 331514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00308 (469/152292) while in subpopulation AFR AF= 0.01 (416/41570). AF 95% confidence interval is 0.00921. There are 1 homozygotes in gnomad4. There are 202 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.3826C>A	p.Pro1276Thr	missense_variant	35/182	ENST00000427231.7
NEB	NM_001164508.2	c.3826C>A	p.Pro1276Thr	missense_variant	35/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.3826C>A	p.Pro1276Thr	missense_variant	35/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.3826C>A	p.Pro1276Thr	missense_variant	35/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.3826C>A	p.Pro1276Thr	missense_variant	35/150	5

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00999

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.000824 AC: 182 AN: 220918 Hom.: 0 AF XY: 0.000582 AC XY: 69 AN XY: 118478

Gnomad AFR exome AF: 0.00906

Gnomad AMR exome AF: 0.00143

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000720

Gnomad OTH exome AF: 0.000542

GnomAD4 exome AF: 0.000438 AC: 632 AN: 1442410 Hom.: 1 Cov.: 30 AF XY: 0.000415 AC XY: 297 AN XY: 715494

Gnomad4 AFR exome AF: 0.0115

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000966

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000863

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00271 AC XY: 202 AN XY: 74466

Gnomad4 AFR AF: 0.0100

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.000500 Hom.: 0

Bravo AF: 0.00370

ESP6500AA AF: 0.0111 AC: 42

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000904 AC: 109

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	NEB: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 28, 2017	- -

Nemaline myopathy 2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.15
Eigen_PC	Benign	0.012
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;.;.
MetaRNN	Benign	0.011	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.;L;L;L;L
MutationTaster	Benign	0.99	D;D;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.1	D;D;.;D;D;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.0060	D;D;.;D;D;.;.
Sift4G	Benign	0.11	T;T;T;T;T;T;T
Polyphen		0.0060	.;.;.;.;B;.;.
Vest4		0.57
MVP		0.35
MPC		0.071
ClinPred		0.039	T
GERP RS		4.6
Varity_R		0.27
gMVP		0.25

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: rs34234609; hg19: chr2-152531854;