rs115708584

Variant names:

• chr10-20961672-A-G
• rs115708584
• ENST00000417816.2:c.357T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001377322.1(NEBL):​c.357T>C​(p.Asn119Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,602,118 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (9 hom.)
• Consequence: NEBL NM_001377322.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001460
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.75
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 10-20961672-A-G is Benign according to our data. Variant chr10-20961672-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 164773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00654 (996/152240) while in subpopulation AFR AF = 0.0228 (948/41540). AF 95% confidence interval is 0.0216. There are 6 homozygotes in GnomAd4. There are 484 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 996 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377322.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	NM_001377322.1		c.357T>C	p.Asn119Asn	splice_region synonymous	Exon 4 of 8	NP_001364251.1
	NEBL	NM_213569.2		c.357T>C	p.Asn119Asn	splice_region synonymous	Exon 4 of 7	NP_998734.1
	NEBL	NM_001377323.1		c.309T>C	p.Asn103Asn	splice_region synonymous	Exon 4 of 7	NP_001364252.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	ENST00000417816.2	TSL:1	c.357T>C	p.Asn119Asn	splice_region synonymous	Exon 4 of 7	ENSP00000393896.2
	NEBL	ENST00000674777.1		n.171T>C		splice_region non_coding_transcript_exon	Exon 2 of 2
	NEBL	ENST00000675114.1		n.565T>C		splice_region non_coding_transcript_exon	Exon 6 of 9

Frequencies

GnomAD3 genomes AF: 0.00657 AC: 1000 AN: 152122 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00183 AC: 460 AN: 251106 AF XY: 0.00131

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000658 AC: 954 AN: 1449878 Hom.: 9 Cov.: 28 AF XY: 0.000546 AC XY: 394 AN XY: 722160

African (AFR) AF: 0.0239 AC: 795 AN: 33206

American (AMR) AF: 0.00121 AC: 54 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5740

European-Non Finnish (NFE) AF: 0.0000200 AC: 22 AN: 1101164

Other (OTH) AF: 0.00128 AC: 77 AN: 60006

GnomAD4 genome AF: 0.00654 AC: 996 AN: 152240 Hom.: 6 Cov.: 32 AF XY: 0.00650 AC XY: 484 AN XY: 74440

African (AFR) AF: 0.0228 AC: 948 AN: 41540

American (AMR) AF: 0.00203 AC: 31 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68014

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00264 Hom.: 6

Bravo AF: 0.00763

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	NEBL-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.1
DANN	Benign	0.49
PhyloP100		-1.7
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.090		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: rs115708584; hg19: chr10-21250601;