rs11902616

chr2-151610487-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164507.2(NEB):c.12018+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 1,540,414 control chromosomes in the GnomAD database, including 6,098 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2289 hom., cov: 32)
  • Exomes 𝑓: 0.039 (3809 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.494

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-151610487-C-T is Benign according to our data. Variant chr2-151610487-C-T is described in ClinVar as [Benign]. Clinvar id is 257726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.12018+29G>A		intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.12018+29G>A		intron_variant		ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.12018+29G>A		intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.12018+29G>A		intron_variant		5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11289+29G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17374 AN: 151940 Hom.: 2268 Cov.: 32

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0572

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0994

GnomAD3 exomes AF: 0.0659 AC: 16298 AN: 247142 Hom.: 1469 AF XY: 0.0654 AC XY: 8762 AN XY: 134012

Gnomad AFR exome AF: 0.327

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.0614

Gnomad EAS exome AF: 0.169

Gnomad SAS exome AF: 0.136

Gnomad FIN exome AF: 0.0153

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.0484

GnomAD4 exome AF: 0.0393 AC: 54577 AN: 1388356 Hom.: 3809 Cov.: 26 AF XY: 0.0414 AC XY: 28766 AN XY: 694708

Gnomad4 AFR exome AF: 0.339

Gnomad4 AMR exome AF: 0.0282

Gnomad4 ASJ exome AF: 0.0639

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0614

GnomAD4 genome AF: 0.115 AC: 17460 AN: 152058 Hom.: 2289 Cov.: 32 AF XY: 0.114 AC XY: 8491 AN XY: 74352

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.0571

Gnomad4 ASJ AF: 0.0637

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.0166

Gnomad4 NFE AF: 0.0183

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0400 Hom.: 450

Bravo AF: 0.126

Asia WGS AF: 0.215 AC: 745 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Nemaline myopathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Arthrogryposis multiplex congenita 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	5.3
Dann	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs11902616; hg19: chr2-152467001; COSMIC: COSV50807631;