rs377648518

Variant names:

• chr10-21173750-C-A
• rs377648518
• ENST00000417816.2:c.69+15G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000417816.2(NEBL):​c.69+15G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000912 in 1,612,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: NEBL ENST00000417816.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.440
• 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-AS1 (HGNC:44899): (NEBL antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 10-21173750-C-A is Benign according to our data. Variant chr10-21173750-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 164778.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_001377324.1	c.-75G>T		5_prime_UTR_variant	Exon 1 of 7		NP_001364253.1
NEBL	NM_001377322.1	c.69+15G>T		intron_variant	Intron 1 of 7		NP_001364251.1
NEBL	NM_213569.2	c.69+15G>T		intron_variant	Intron 1 of 6		NP_998734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000417816.2	c.69+15G>T		intron_variant	Intron 1 of 6	1		ENSP00000393896.2
NEBL-AS1	ENST00000737815.1	n.152C>A		non_coding_transcript_exon_variant	Exon 1 of 2
NEBL	ENST00000464278.1	n.74+15G>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000162 AC: 40 AN: 247306 AF XY: 0.000164

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.0000897 AC: 131 AN: 1460448 Hom.: 0 Cov.: 32 AF XY: 0.0000908 AC XY: 66 AN XY: 726588

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00306 AC: 80 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111804

Other (OTH) AF: 0.000265 AC: 16 AN: 60370

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74294

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.000117

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

69+15G>T in intron 1 of NEBL: This variant is not expected to have clinical sign ificance because it is not located within the splice consensus sequence. It has been identified in 2/7020 European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). 69+15 G>T in intron 1 of NEBL (allele frequency = 2/7020) ** -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.95
PhyloP100		0.44
PromoterAI		0.020	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs377648518; hg19: chr10-21462679;