rs397718862

Variant names:

• chr2-151717388-A-AGGC
• rs397718862
• NM_001164507.2:c.822+25_822+27dupGCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001164507.2(NEB):​c.822+25_822+27dupGCC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (38670 hom., cov: 0)
  • Exomes 𝑓: 0.79 (405711 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.499
• Publications: 1 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

ACMG classification

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

• BP6: Variant 2-151717388-A-AGGC is Benign according to our data. Variant chr2-151717388-A-AGGC is described in ClinVar as Benign. ClinVar VariationId is 257832.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.822+25_822+27dupGCC		intron_variant	Intron 10 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.822+25_822+27dupGCC		intron_variant	Intron 10 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.822+27_822+28insGCC		intron_variant	Intron 10 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.822+27_822+28insGCC		intron_variant	Intron 10 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.822+27_822+28insGCC		intron_variant	Intron 10 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103287 AN: 151722 Hom.: 38664 Cov.: 0

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.860

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.723

GnomAD2 exomes AF: 0.754 AC: 183267 AN: 243122 AF XY: 0.756

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.862

Gnomad ASJ exome AF: 0.737

Gnomad EAS exome AF: 0.473

Gnomad FIN exome AF: 0.851

Gnomad NFE exome AF: 0.834

Gnomad OTH exome AF: 0.786

GnomAD4 exome AF: 0.790 AC: 1004056 AN: 1271144 Hom.: 405711 Cov.: 20 AF XY: 0.788 AC XY: 505748 AN XY: 641958

African (AFR) AF: 0.338 AC: 10370 AN: 30704

American (AMR) AF: 0.855 AC: 37568 AN: 43944

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 18367 AN: 24974

East Asian (EAS) AF: 0.437 AC: 17017 AN: 38932

South Asian (SAS) AF: 0.651 AC: 53409 AN: 82008

European-Finnish (FIN) AF: 0.850 AC: 45139 AN: 53116

Middle Eastern (MID) AF: 0.771 AC: 4190 AN: 5436

European-Non Finnish (NFE) AF: 0.829 AC: 777081 AN: 937714

Other (OTH) AF: 0.753 AC: 40915 AN: 54316

GnomAD4 genome AF: 0.680 AC: 103305 AN: 151842 Hom.: 38670 Cov.: 0 AF XY: 0.684 AC XY: 50735 AN XY: 74226

African (AFR) AF: 0.356 AC: 14743 AN: 41370

American (AMR) AF: 0.811 AC: 12379 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 2521 AN: 3466

East Asian (EAS) AF: 0.457 AC: 2355 AN: 5156

South Asian (SAS) AF: 0.650 AC: 3130 AN: 4812

European-Finnish (FIN) AF: 0.860 AC: 9069 AN: 10548

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.834 AC: 56609 AN: 67910

Other (OTH) AF: 0.714 AC: 1506 AN: 2108

Alfa AF: 0.771 Hom.: 10404

Asia WGS AF: 0.497 AC: 1733 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397718862; hg19: chr2-152573902;