10-20828531-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006393.3(NEBL):c.1775C>G(p.Ala592Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/23 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A592E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEBL NM_006393.3 missense, splice_region
• Scores: Splicing: ADA: 0.0002462
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.495

Genes affected

NEBL (HGNC:16932): (nebulette) This gene encodes a nebulin like protein that is abundantly expressed in cardiac muscle. The encoded protein binds actin and interacts with thin filaments and Z-line associated proteins in striated muscle. This protein may be involved in cardiac myofibril assembly. A shorter isoform of this protein termed LIM nebulette is expressed in non-muscle cells and may function as a component of focal adhesion complexes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061233014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3	c.1775C>G	p.Ala592Gly	missense_variant, splice_region_variant	17/28	ENST00000377122.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9	c.1775C>G	p.Ala592Gly	missense_variant, splice_region_variant	17/28	1	NM_006393.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	6.9
Dann	Benign	0.81
DEOGEN2	Benign	0.0076	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.039	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.63	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.025
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.036	D
Polyphen		0.013	B
Vest4		0.23
MutPred		0.40		Gain of glycosylation at S591 (P = 0.0423);
MVP		0.15
MPC		0.016
ClinPred		0.10	T
GERP RS		-2.5
Varity_R		0.068
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.074
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: rs146275785; hg19: chr10-21117460;