chr10-20828531-G-C

Variant names:

• chr10-20828531-G-C
• rs146275785
• NM_006393.3:c.1775C>G

Variant summary

Our verdict is Likely benign. The variant received -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. 18/24 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. A592V) 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
• Publications: 9 publications found

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]

NEBL Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006393.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	NM_006393.3	MANE Select	c.1775C>G	p.Ala592Gly	missense splice_region	Exon 17 of 28	NP_006384.1
	NEBL	NM_001377322.1		c.358-15591C>G		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.358-15591C>G		intron	N/A	NP_998734.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	ENST00000377122.9	TSL:1 MANE Select	c.1775C>G	p.Ala592Gly	missense splice_region	Exon 17 of 28	ENSP00000366326.4
	NEBL	ENST00000493005.5	TSL:1	n.375C>G		splice_region non_coding_transcript_exon	Exon 4 of 12
	NEBL	ENST00000417816.2	TSL:1	c.358-15591C>G		intron	N/A	ENSP00000393896.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.49
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
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs146275785; hg19: chr10-21117460;