rs2288201

Variant names:

• chr2-151547780-C-T
• rs2288201
• NM_001164507.2:c.20158-42G>A

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.20158-42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,421,254 control chromosomes in the GnomAD database, including 288,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30717 hom., cov: 31)
  • Exomes 𝑓: 0.63 (257510 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.125
• Publications: 7 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=-0.9).
• BP6: Variant 2-151547780-C-T is Benign according to our data. Variant chr2-151547780-C-T is described in ClinVar as Benign. ClinVar VariationId is 257783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.20158-42G>A		intron_variant	Intron 131 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.20158-42G>A		intron_variant	Intron 131 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.20158-42G>A		intron_variant	Intron 131 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.20158-42G>A		intron_variant	Intron 131 of 181	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96048 AN: 151646 Hom.: 30670 Cov.: 31

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.716

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.771

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.676

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.639

GnomAD2 exomes AF: 0.642 AC: 133760 AN: 208318 AF XY: 0.631

Gnomad AFR exome AF: 0.610

Gnomad AMR exome AF: 0.752

Gnomad ASJ exome AF: 0.540

Gnomad EAS exome AF: 0.777

Gnomad FIN exome AF: 0.665

Gnomad NFE exome AF: 0.635

Gnomad OTH exome AF: 0.649

GnomAD4 exome AF: 0.635 AC: 805915 AN: 1269490 Hom.: 257510 Cov.: 17 AF XY: 0.629 AC XY: 400223 AN XY: 636424

African (AFR) AF: 0.611 AC: 17823 AN: 29166

American (AMR) AF: 0.741 AC: 29234 AN: 39466

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 12905 AN: 24276

East Asian (EAS) AF: 0.793 AC: 30135 AN: 38020

South Asian (SAS) AF: 0.491 AC: 38393 AN: 78168

European-Finnish (FIN) AF: 0.664 AC: 34531 AN: 51970

Middle Eastern (MID) AF: 0.617 AC: 3313 AN: 5366

European-Non Finnish (NFE) AF: 0.638 AC: 605417 AN: 949100

Other (OTH) AF: 0.633 AC: 34164 AN: 53958

GnomAD4 genome AF: 0.634 AC: 96156 AN: 151764 Hom.: 30717 Cov.: 31 AF XY: 0.636 AC XY: 47186 AN XY: 74148

African (AFR) AF: 0.604 AC: 24951 AN: 41332

American (AMR) AF: 0.716 AC: 10918 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1844 AN: 3464

East Asian (EAS) AF: 0.770 AC: 3985 AN: 5174

South Asian (SAS) AF: 0.502 AC: 2411 AN: 4800

European-Finnish (FIN) AF: 0.676 AC: 7095 AN: 10502

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.632 AC: 42961 AN: 67938

Other (OTH) AF: 0.644 AC: 1358 AN: 2110

Alfa AF: 0.632 Hom.: 5794

Bravo AF: 0.640

Asia WGS AF: 0.630 AC: 2193 AN: 3478

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	-0.90
CADD	Benign	1.6
DANN	Benign	0.71
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs2288201; hg19: chr2-152404294;