rs377452683

Variant names:

• chr2-151727801-ATGCTGGCTGTGCCAG-A
• rs377452683
• NM_001164507.2:c.169_183delCTGGCACAGCCAGCA

Your query was ambiguous. Multiple possible variants found:

• chr2-151727801-ATGCTGGCTGTGCCAG-A
• chr2-151727801-ATGCTGGCTGTGCCAG-ATGCTGGCTGTGCCAGTGCTGGCTGTGCCAG
• chr2-151727801-ATGCTGGCTGTGCCAG-ATGCTGGCTGTGCCAGTGCTGGCTGTGCCAGTGCTGGCTGTGCCAG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.169_183delCTGGCACAGCCAGCA​(p.Leu57_Ala61del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,611,950 control chromosomes in the GnomAD database, including 100 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (53 hom.)
• Consequence: NEB NM_001164507.2 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.20
• 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001164507.2
• BP6: Variant 2-151727801-ATGCTGGCTGTGCCAG-A is Benign according to our data. Variant chr2-151727801-ATGCTGGCTGTGCCAG-A is described in ClinVar as Benign. ClinVar VariationId is 95115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0146 (2222/152156) while in subpopulation AFR AF = 0.0448 (1859/41514). AF 95% confidence interval is 0.0431. There are 47 homozygotes in GnomAd4. There are 1067 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	Exon 5 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	Exon 5 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	Exon 5 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	Exon 5 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	Exon 5 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	Exon 5 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2219 AN: 152038 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00520 AC: 1291 AN: 248352 AF XY: 0.00432

Gnomad AFR exome AF: 0.0468

Gnomad AMR exome AF: 0.00410

Gnomad ASJ exome AF: 0.000895

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00423

Gnomad NFE exome AF: 0.00269

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00352 AC: 5136 AN: 1459794 Hom.: 53 AF XY: 0.00327 AC XY: 2375 AN XY: 726068

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0484 AC: 1618 AN: 33428

American (AMR) AF: 0.00424 AC: 189 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000269 AC: 23 AN: 85612

European-Finnish (FIN) AF: 0.00412 AC: 220 AN: 53392

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5744

European-Non Finnish (NFE) AF: 0.00245 AC: 2718 AN: 1110896

Other (OTH) AF: 0.00486 AC: 293 AN: 60278

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0146 AC: 2222 AN: 152156 Hom.: 47 Cov.: 32 AF XY: 0.0143 AC XY: 1067 AN XY: 74396

African (AFR) AF: 0.0448 AC: 1859 AN: 41514

American (AMR) AF: 0.00674 AC: 103 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

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

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4768

European-Finnish (FIN) AF: 0.00537 AC: 57 AN: 10612

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00251 AC: 171 AN: 68016

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.000960 Hom.: 0

Bravo AF: 0.0157

EpiCase AF: 0.00202

EpiControl AF: 0.00214

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Nemaline myopathy 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=200/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs377452683; hg19: chr2-152584315;