rs4748728

Variant names:

• chr10-20823208-A-T
• rs4748728
• NM_006393.3:c.1962T>A

Your query was ambiguous. Multiple possible variants found:

• chr10-20823208-A-T
• chr10-20823208-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006393.3(NEBL):​c.1962T>A​(p.Asn654Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,596,352 control chromosomes in the GnomAD database, including 3,014 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N654I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.079 (901 hom., cov: 32)
  • Exomes 𝑓: 0.034 (2113 hom.)
• Consequence: NEBL NM_006393.3 missense, splice_region
• Scores: Splicing: ADA: 0.6236
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.915
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017476678).
• BP6: Variant 10-20823208-A-T is Benign according to our data. Variant chr10-20823208-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	NM_006393.3	MANE Select	c.1962T>A	p.Asn654Lys	missense splice_region	Exon 19 of 28	NP_006384.1	O76041-1
	NEBL	NM_001377322.1		c.358-10268T>A		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.358-10268T>A		intron	N/A	NP_998734.1	Q59FZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	ENST00000377122.9	TSL:1 MANE Select	c.1962T>A	p.Asn654Lys	missense splice_region	Exon 19 of 28	ENSP00000366326.4	O76041-1
	NEBL	ENST00000417816.2	TSL:1	c.358-10268T>A		intron	N/A	ENSP00000393896.2	O76041-2
	NEBL	ENST00000493005.5	TSL:1	n.562T>A		splice_region non_coding_transcript_exon	Exon 6 of 12

Frequencies

GnomAD3 genomes AF: 0.0787 AC: 11969 AN: 152112 Hom.: 889 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0671

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.0942

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0751

GnomAD2 exomes AF: 0.0565 AC: 14044 AN: 248674 AF XY: 0.0543

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0720

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.114

Gnomad FIN exome AF: 0.0281

Gnomad NFE exome AF: 0.0220

Gnomad OTH exome AF: 0.0414

GnomAD4 exome AF: 0.0340 AC: 49110 AN: 1444122 Hom.: 2113 Cov.: 29 AF XY: 0.0351 AC XY: 25265 AN XY: 719334

African (AFR) AF: 0.204 AC: 6744 AN: 32996

American (AMR) AF: 0.0728 AC: 3246 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.0174 AC: 453 AN: 26016

East Asian (EAS) AF: 0.137 AC: 5401 AN: 39454

South Asian (SAS) AF: 0.0893 AC: 7646 AN: 85646

European-Finnish (FIN) AF: 0.0262 AC: 1338 AN: 51094

Middle Eastern (MID) AF: 0.0534 AC: 252 AN: 4722

European-Non Finnish (NFE) AF: 0.0194 AC: 21289 AN: 1099858

Other (OTH) AF: 0.0459 AC: 2741 AN: 59722

GnomAD4 genome AF: 0.0790 AC: 12021 AN: 152230 Hom.: 901 Cov.: 32 AF XY: 0.0789 AC XY: 5875 AN XY: 74428

African (AFR) AF: 0.192 AC: 7980 AN: 41500

American (AMR) AF: 0.0669 AC: 1024 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 46 AN: 3472

East Asian (EAS) AF: 0.118 AC: 609 AN: 5180

South Asian (SAS) AF: 0.0945 AC: 455 AN: 4816

European-Finnish (FIN) AF: 0.0266 AC: 282 AN: 10614

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1436 AN: 68028

Other (OTH) AF: 0.0814 AC: 172 AN: 2112

Alfa AF: 0.0308 Hom.: 250

Bravo AF: 0.0887

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.192 AC: 848

ESP6500EA AF: 0.0224 AC: 193

ExAC AF: 0.0593 AC: 7204

Asia WGS AF: 0.160 AC: 560 AN: 3478

EpiCase AF: 0.0246

EpiControl AF: 0.0242

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	NEBL-related disorder (1)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0062	T
Eigen	Benign	0.0089
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.92
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.082
Sift	Benign	0.057	T
Sift4G	Benign	0.20	T
Polyphen		0.032	B
Vest4		0.061
MutPred		0.24		Loss of ubiquitination at K650 (P = 0.0162)
MPC		0.017
ClinPred		0.022	T
GERP RS		4.8
Varity_R		0.14
gMVP		0.19
Mutation Taster		=81/19	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.62
SpliceAI score (max)		0.060		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: rs4748728; hg19: chr10-21112137; COSMIC: COSV65806282; COSMIC: COSV65806282;