rs767858255

chr2-151610065-C-Achr2-151610065-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001164507.2(NEB):c.12074G>T(p.Ser4025Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S4025S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.35

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13525197).
• BP6: Variant 2-151610065-C-A is Benign according to our data. Variant chr2-151610065-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465442.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	UniProt
NEB	NM_001164507.2	c.12074G>T	p.Ser4025Ile	missense_variant	81/182	ENST00000427231.7
NEB	NM_001164508.2	c.12074G>T	p.Ser4025Ile	missense_variant	81/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.12074G>T	p.Ser4025Ile	missense_variant	81/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.12074G>T	p.Ser4025Ile	missense_variant	81/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11345G>T	p.Ser3782Ile	missense_variant	78/150	5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000402 AC: 10 AN: 248666 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000465 AC: 68 AN: 1461578 Hom.: 0 Cov.: 32 AF XY: 0.0000495 AC XY: 36 AN XY: 727068

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152142 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74320

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.11345G>T (p.S3782I) alteration is located in exon 78 (coding exon 76) of the NEB gene. This alteration results from a G to T substitution at nucleotide position 11345, causing the serine (S) at amino acid position 3782 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Nemaline myopathy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.0039
Eigen_PC	Benign	-0.0082
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.73	T;T;D;T;T;.;.
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M;.;.;.;M;.;.
MutationTaster	Benign	0.99	D;D;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N;N;.;N;N;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.0060	D;D;.;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		0.35	.;.;.;.;B;.;.
Vest4		0.39
MVP		0.35
MPC		0.23
ClinPred		0.32	T
GERP RS		5.4
Varity_R		0.34
gMVP		0.40

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: rs767858255; hg19: chr2-152466579;