rs3732310

chr2-151538020-T-G

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.20998-44A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 1,556,572 control chromosomes in the GnomAD database, including 289,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24954 hom., cov: 31)
  • Exomes 𝑓: 0.61 (264180 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.981

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]

LOC124906081 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-151538020-T-G is Benign according to our data. Variant chr2-151538020-T-G is described in ClinVar as [Benign]. Clinvar id is 257786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151538020-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.20998-44A>C		intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.20998-44A>C		intron_variant		ENST00000397345.8
LOC124906081	XR_007087266.1	n.245T>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.20998-44A>C		intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.20998-44A>C		intron_variant		5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85473 AN: 151796 Hom.: 24930 Cov.: 31

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.569

GnomAD3 exomes AF: 0.594 AC: 142719 AN: 240394 Hom.: 43470 AF XY: 0.584 AC XY: 76055 AN XY: 130268

Gnomad AFR exome AF: 0.418

Gnomad AMR exome AF: 0.728

Gnomad ASJ exome AF: 0.528

Gnomad EAS exome AF: 0.582

Gnomad SAS exome AF: 0.411

Gnomad FIN exome AF: 0.641

Gnomad NFE exome AF: 0.623

Gnomad OTH exome AF: 0.612

GnomAD4 exome AF: 0.609 AC: 855624 AN: 1404658 Hom.: 264180 Cov.: 23 AF XY: 0.603 AC XY: 422547 AN XY: 701198

Gnomad4 AFR exome AF: 0.414

Gnomad4 AMR exome AF: 0.719

Gnomad4 ASJ exome AF: 0.524

Gnomad4 EAS exome AF: 0.628

Gnomad4 SAS exome AF: 0.411

Gnomad4 FIN exome AF: 0.641

Gnomad4 NFE exome AF: 0.627

Gnomad4 OTH exome AF: 0.594

GnomAD4 genome AF: 0.563 AC: 85529 AN: 151914 Hom.: 24954 Cov.: 31 AF XY: 0.564 AC XY: 41881 AN XY: 74230

Gnomad4 AFR AF: 0.416

Gnomad4 AMR AF: 0.684

Gnomad4 ASJ AF: 0.513

Gnomad4 EAS AF: 0.583

Gnomad4 SAS AF: 0.404

Gnomad4 FIN AF: 0.644

Gnomad4 NFE AF: 0.625

Gnomad4 OTH AF: 0.563

Alfa AF: 0.591 Hom.: 5473

Bravo AF: 0.565

Asia WGS AF: 0.452 AC: 1574 AN: 3476

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	-0.78
Cadd	Benign	6.1
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs3732310; hg19: chr2-152394534; COSMIC: COSV51437783;