rs199887353

Variant names:

• chr10-20787295-G-A
• rs199887353
• NM_006393.3:c.2775C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_006393.3(NEBL):​c.2775C>T​(p.Pro925Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,612,436 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: NEBL NM_006393.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.951
• Publications: 1 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 10-20787295-G-A is Benign according to our data. Variant chr10-20787295-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 227736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.951 with no splicing effect.
• BS2: High AC in GnomAd4 at 24 AD gene.

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.2775C>T	p.Pro925Pro	synonymous	Exon 27 of 28	NP_006384.1
	NEBL	NM_001377322.1		c.636C>T	p.Pro212Pro	synonymous	Exon 7 of 8	NP_001364251.1
	NEBL	NM_213569.2		c.543C>T	p.Pro181Pro	synonymous	Exon 6 of 7	NP_998734.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	ENST00000377122.9	TSL:1 MANE Select	c.2775C>T	p.Pro925Pro	synonymous	Exon 27 of 28	ENSP00000366326.4
	NEBL	ENST00000417816.2	TSL:1	c.543C>T	p.Pro181Pro	synonymous	Exon 6 of 7	ENSP00000393896.2
	NEBL	ENST00000676125.1		c.572C>T	p.Pro191Leu	missense	Exon 7 of 8	ENSP00000501594.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152090 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 249742 AF XY: 0.0000815

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1460346 Hom.: 1 Cov.: 31 AF XY: 0.000107 AC XY: 78 AN XY: 726404

African (AFR) AF: 0.000239 AC: 8 AN: 33438

American (AMR) AF: 0.0000896 AC: 4 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000132 AC: 147 AN: 1111098

Other (OTH) AF: 0.0000663 AC: 4 AN: 60334

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152090 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74286

African (AFR) AF: 0.000314 AC: 13 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000117

EpiCase AF: 0.000164

EpiControl AF: 0.000238

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.8
DANN	Benign	0.62
PhyloP100		0.95
Mutation Taster		=99/1	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: rs199887353; hg19: chr10-21076224; COSMIC: COSV101009145;