rs150000482

Variant names:

• chr10-20889889-G-C
• rs150000482
• NM_006393.3:c.214C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-20889889-G-C
• chr10-20889889-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006393.3(NEBL):​c.214C>G​(p.Pro72Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. P72T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NEBL NM_006393.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_006393.3	c.214C>G	p.Pro72Ala	missense_variant	Exon 3 of 28	ENST00000377122.9	NP_006384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9	c.214C>G	p.Pro72Ala	missense_variant	Exon 3 of 28	1	NM_006393.3	ENSP00000366326.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460758 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726734

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111192

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0068	T
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		7.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.023	D;T
Sift4G	Benign	0.72	T;.
Vest4		0.74
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.35
gMVP		0.32
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs150000482; hg19: chr10-21178818; COSMIC: COSV65799971;