2-151538020-T-G

Variant names:

• chr2-151538020-T-G
• rs3732310
• NM_001164507.2:c.20998-44A>C

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: 0.981
• Publications: 9 publications found

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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124906081 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.20998-44A>C		intron_variant	Intron 139 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.20998-44A>C		intron_variant	Intron 139 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.20998-44A>C		intron_variant	Intron 139 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.20998-44A>C		intron_variant	Intron 139 of 181	5	NM_001164507.2	ENSP00000416578.2

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

GnomAD2 exomes AF: 0.594 AC: 142719 AN: 240394 AF XY: 0.584

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 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

African (AFR) AF: 0.414 AC: 13255 AN: 32004

American (AMR) AF: 0.719 AC: 31340 AN: 43578

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 13415 AN: 25622

East Asian (EAS) AF: 0.628 AC: 24647 AN: 39256

South Asian (SAS) AF: 0.411 AC: 34382 AN: 83722

European-Finnish (FIN) AF: 0.641 AC: 34074 AN: 53158

Middle Eastern (MID) AF: 0.604 AC: 3421 AN: 5668

European-Non Finnish (NFE) AF: 0.627 AC: 666352 AN: 1063144

Other (OTH) AF: 0.594 AC: 34738 AN: 58506

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

African (AFR) AF: 0.416 AC: 17245 AN: 41414

American (AMR) AF: 0.684 AC: 10444 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1781 AN: 3472

East Asian (EAS) AF: 0.583 AC: 3012 AN: 5166

South Asian (SAS) AF: 0.404 AC: 1943 AN: 4810

European-Finnish (FIN) AF: 0.644 AC: 6768 AN: 10514

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42501 AN: 67972

Other (OTH) AF: 0.563 AC: 1184 AN: 2104

Alfa AF: 0.587 Hom.: 5547

Bravo AF: 0.565

Asia WGS AF: 0.452 AC: 1574 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nemaline myopathy 2 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis multiplex congenita 6 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.1
DANN	Benign	0.71
PhyloP100		0.98
Mutation Taster		=100/0	polymorphism (auto)

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