2-151552672-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164507.2(NEB):c.19836C>A(p.Asp6612Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D6612D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NEB NM_001164507.2 missense, splice_region
• Scores: Splicing: ADA: 0.00003709
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.596

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17331594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.19836C>A	p.Asp6612Glu	missense_variant, splice_region_variant	128/182	ENST00000427231.7
NEB	NM_001164508.2	c.19836C>A	p.Asp6612Glu	missense_variant, splice_region_variant	128/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.19836C>A	p.Asp6612Glu	missense_variant, splice_region_variant	128/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.19836C>A	p.Asp6612Glu	missense_variant, splice_region_variant	128/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247232 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134026

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

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 AF: 6.87e-7 AC: 1 AN: 1455280 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	1.9
Dann	Benign	0.96
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.80	T;T;T;T;T;T;.;.
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;.;.;.;N;.;.;.
MutationTaster	Benign	0.98	D;D;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N;N;.;N;N;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.42	T;T;.;T;T;T;.;.
Sift4G	Benign	0.62	T;T;T;T;T;T;T;T
Polyphen		0.11	.;.;.;.;B;.;.;.
Vest4		0.18
MutPred		0.65		Gain of catalytic residue at D4911 (P = 0.0112);.;.;.;Gain of catalytic residue at D4911 (P = 0.0112);.;.;.;
MVP		0.25
MPC		0.14
ClinPred		0.20	T
GERP RS		-3.7
Varity_R		0.11
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.026
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: rs371194689; hg19: chr2-152409186;