rs778982089

Positions:

• chr2-151567424-G-A

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.17900C>T​(p.Thr5967Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. T5967T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.25

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25363415).
• BP6: Variant 2-151567424-G-A is Benign according to our data. Variant chr2-151567424-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 571969.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.17900C>T	p.Thr5967Met	missense_variant	114/182	ENST00000427231.7
NEB	NM_001164508.2	c.17900C>T	p.Thr5967Met	missense_variant	114/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.17900C>T	p.Thr5967Met	missense_variant	114/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.17900C>T	p.Thr5967Met	missense_variant	114/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000604 AC: 15 AN: 248290 Hom.: 0 AF XY: 0.0000520 AC XY: 7 AN XY: 134670

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000890 AC: 130 AN: 1461312 Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 62 AN XY: 726898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74258

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.0000248 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 19, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;.;.
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.7	L;.;.;.;L;.;.;.
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N;N;.;N;N;D;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D;D;.;D;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		0.99	.;.;.;.;D;.;.;.
Vest4		0.56
MVP		0.48
MPC		0.33
ClinPred		0.33	T
GERP RS		5.0
Varity_R		0.11
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778982089; hg19: chr2-152423938;