rs750810441

Positions:

• chr2-151581575-C-G
• chr2-151581575-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001164507.2(NEB):​c.16192G>C​(p.Asp5398His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D5398N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3180327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.16192G>C	p.Asp5398His	missense_variant	103/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.16192G>C	p.Asp5398His	missense_variant	103/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.16192G>C	p.Asp5398His	missense_variant	103/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.16192G>C	p.Asp5398His	missense_variant	103/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000413693.5	c.382G>C	p.Asp128His	missense_variant	3/74	5		ENSP00000410961
NEB	ENST00000409198.5	c.11602-5221G>C		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000138 AC: 1 AN: 726024 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 379496

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000203

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

NEB: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.013	.;T;.;T;.;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T;T;T;.;.
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.32	T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-0.61	N;.;N;N;.;.
REVEL	Benign	0.066
Sift	Benign	0.034	D;.;D;T;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;D;D
Vest4		0.30
MutPred		0.34		Loss of phosphorylation at Y5396 (P = 0.1245);Loss of phosphorylation at Y5396 (P = 0.1245);Loss of phosphorylation at Y5396 (P = 0.1245);.;Loss of phosphorylation at Y5396 (P = 0.1245);Loss of phosphorylation at Y5396 (P = 0.1245);
MVP		0.66
MPC		0.36
ClinPred		0.69	D
GERP RS		4.3
gMVP		0.017

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: rs750810441; hg19: chr2-152438089;