rs11436831

Variant names:

• chr2-151591331-G-GC
• rs11436831
• NM_001164507.2:c.14934+16_14934+17insG

Your query was ambiguous. Multiple possible variants found:

• chr2-151591331-G-GC
• chr2-151591331-G-GT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001164507.2(NEB):​c.14934+16_14934+17insG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (17 hom., cov: 19)
  • Exomes 𝑓: 0.26 (86 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.152
• Publications: 2 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 -12 ACMG points.

• BP6: Variant 2-151591331-G-GC is Benign according to our data. Variant chr2-151591331-G-GC is described in ClinVar as Benign. ClinVar VariationId is 257749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.14934+16_14934+17insG		intron_variant	Intron 96 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.14934+16_14934+17insG		intron_variant	Intron 96 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.14934+16_14934+17insG		intron_variant	Intron 96 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.14934+16_14934+17insG		intron_variant	Intron 96 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.11602-14978_11602-14977insG		intron_variant	Intron 78 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 28158 AN: 141824 Hom.: 18 Cov.: 19

Gnomad AFR AF: 0.0668

Gnomad AMI AF: 0.0826

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.240

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.233 AC: 34038 AN: 146294 AF XY: 0.232

Gnomad AFR exome AF: 0.0568

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.202

Gnomad EAS exome AF: 0.241

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.238

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.261 AC: 344280 AN: 1319050 Hom.: 86 Cov.: 33 AF XY: 0.259 AC XY: 168847 AN XY: 651606

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

African (AFR) AF: 0.0636 AC: 1974 AN: 31036

American (AMR) AF: 0.266 AC: 9180 AN: 34540

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 4841 AN: 24116

East Asian (EAS) AF: 0.236 AC: 8076 AN: 34270

South Asian (SAS) AF: 0.183 AC: 14048 AN: 76964

European-Finnish (FIN) AF: 0.257 AC: 11978 AN: 46584

Middle Eastern (MID) AF: 0.228 AC: 897 AN: 3928

European-Non Finnish (NFE) AF: 0.276 AC: 280004 AN: 1012730

Other (OTH) AF: 0.242 AC: 13282 AN: 54882

⚠️ 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: 0.198 AC: 28165 AN: 141936 Hom.: 17 Cov.: 19 AF XY: 0.198 AC XY: 13710 AN XY: 69252

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

African (AFR) AF: 0.0669 AC: 2696 AN: 40312

American (AMR) AF: 0.223 AC: 3126 AN: 14014

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 594 AN: 3230

East Asian (EAS) AF: 0.234 AC: 1145 AN: 4886

South Asian (SAS) AF: 0.169 AC: 759 AN: 4482

European-Finnish (FIN) AF: 0.251 AC: 2411 AN: 9618

Middle Eastern (MID) AF: 0.241 AC: 64 AN: 266

European-Non Finnish (NFE) AF: 0.271 AC: 16890 AN: 62298

Other (OTH) AF: 0.208 AC: 408 AN: 1958

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.186 Hom.: 1

Asia WGS AF: 0.205 AC: 713 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 03, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

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		0.15
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: rs11436831; hg19: chr2-152447845;