2-151677581-G-T

Variant names:

• chr2-151677581-G-T
• rs767433330
• NM_001164507.2:c.3758C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001164508.2(NEB):​c.3758C>A​(p.Thr1253Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.3758C>A	p.Thr1253Lys	missense_variant	Exon 34 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.3758C>A	p.Thr1253Lys	missense_variant	Exon 34 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.3758C>A	p.Thr1253Lys	missense_variant	Exon 34 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.3758C>A	p.Thr1253Lys	missense_variant	Exon 34 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.3758C>A	p.Thr1253Lys	missense_variant	Exon 34 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000804 AC: 2 AN: 248828 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134982

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NEB c.3758C>A (p.Thr1253Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248828 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3758C>A has been reported in the literature in at least one compound heterozygous individual affected with Nemaline Myopathy 2 (e.g., Yin_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33742414). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	.;.;T;.;T;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;D;D;D;T;.;.
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.77	N;N;.;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	N;N;.;N;N;.;.
REVEL	Benign	0.17
Sift	Benign	0.10	T;D;.;T;T;.;.
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D
Polyphen		0.94	.;.;.;.;P;.;.
Vest4		0.51
MutPred		0.54		Gain of methylation at T1253 (P = 0.0314);Gain of methylation at T1253 (P = 0.0314);Gain of methylation at T1253 (P = 0.0314);Gain of methylation at T1253 (P = 0.0314);Gain of methylation at T1253 (P = 0.0314);Gain of methylation at T1253 (P = 0.0314);Gain of methylation at T1253 (P = 0.0314);
MVP		0.66
MPC		0.32
ClinPred		0.88	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.59

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: rs767433330; hg19: chr2-152534095;