rs144077905

Variant names:

• chr2-151552815-C-G
• rs144077905
• NM_001164507.2:c.19732-39G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001164507.2(NEB):​c.19732-39G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00939 in 1,483,466 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0068 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (92 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.315
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-151552815-C-G is Benign according to our data. Variant chr2-151552815-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 257782.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00677 (1030/152250) while in subpopulation NFE AF = 0.0105 (717/68026). AF 95% confidence interval is 0.0099. There are 6 homozygotes in GnomAd4. There are 485 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.19732-39G>C		intron_variant	Intron 127 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.19732-39G>C		intron_variant	Intron 127 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.19732-39G>C		intron_variant	Intron 127 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.19732-39G>C		intron_variant	Intron 127 of 181	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.00677 AC: 1030 AN: 152132 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00924

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00650 AC: 1338 AN: 205942 AF XY: 0.00676

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00537

Gnomad ASJ exome AF: 0.00722

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.00659

GnomAD4 exome AF: 0.00969 AC: 12900 AN: 1331216 Hom.: 92 Cov.: 19 AF XY: 0.00960 AC XY: 6384 AN XY: 665246

African (AFR) AF: 0.00123 AC: 38 AN: 31008

American (AMR) AF: 0.00542 AC: 216 AN: 39816

Ashkenazi Jewish (ASJ) AF: 0.00640 AC: 160 AN: 24994

East Asian (EAS) AF: 0.00 AC: 0 AN: 38292

South Asian (SAS) AF: 0.00509 AC: 409 AN: 80314

European-Finnish (FIN) AF: 0.00218 AC: 113 AN: 51898

Middle Eastern (MID) AF: 0.000905 AC: 5 AN: 5522

European-Non Finnish (NFE) AF: 0.0115 AC: 11501 AN: 1003430

Other (OTH) AF: 0.00819 AC: 458 AN: 55942

GnomAD4 genome AF: 0.00677 AC: 1030 AN: 152250 Hom.: 6 Cov.: 32 AF XY: 0.00652 AC XY: 485 AN XY: 74432

African (AFR) AF: 0.00217 AC: 90 AN: 41550

American (AMR) AF: 0.00922 AC: 141 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4822

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 717 AN: 68026

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00735 Hom.: 0

Bravo AF: 0.00688

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.82
CADD	Benign	2.3
DANN	Benign	0.51
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

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: rs144077905; hg19: chr2-152409329;