Genetic Variant NEB:p.Pro65Leu (chr2-151727790-CG-AA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001164508.2(NEB):c.194_195delCGinsTT (p.Pro65Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P65L: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 229041); p.P65= (synonymous): Likely_benign (ClinVar VariationId 1129905, 1 star); p.P65= (synonymous): Benign/Likely_benign (ClinVar VariationId 95125, 2 stars)

Frequency

Genomes: not found (cov: 33)

Consequence

NEB
NM_001164508.2 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.39

Publications

0 publications found

Variant links:

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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Natera, Myriad Women's Health, Ambry Genetics, ClinGen
autosomal dominant nebulin-related myopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
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

NEB links:

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new If you want to explore the variant's impact on the transcript NM_001164508.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00115) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001164508.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
NEB NM_001164507.2	MANE Plus Clinical	c.194_195delCGinsTT p.Pro65Leu	missense	N/A	Prot: NP_001157979.2 UniProt: P20929-3
NEB NM_001164508.2	MANE Select	c.194_195delCGinsTT p.Pro65Leu	missense	N/A	Prot: NP_001157980.2 UniProt: P20929-2
NEB NM_001271208.2		c.194_195delCGinsTT p.Pro65Leu	missense	N/A	Prot: NP_001258137.2

NEB NM_001164507.2

MANE Plus Clinical

HGVSc / HGVSpc.194_195delCGinsTTp.Pro65Leu

Exon rankN/A

missense

Prot: NP_001157979.2UniProt: P20929-3

NEB NM_001164508.2

MANE Select

HGVSc / HGVSpc.194_195delCGinsTTp.Pro65Leu

Exon rankN/A

missense

Prot: NP_001157980.2UniProt: P20929-2

NEB NM_001271208.2

HGVSc / HGVSpc.194_195delCGinsTTp.Pro65Leu

Exon rankN/A

missense

Prot: NP_001258137.2

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
NEB ENST00000397345.8	TSL:5MANE Select	c.194_195delCGinsTT p.Pro65Leu	missense	N/A	Prot: ENSP00000380505.3 UniProt: P20929-2
NEB ENST00000427231.7	TSL:5MANE Plus Clinical	c.194_195delCGinsTT p.Pro65Leu	missense	N/A	Prot: ENSP00000416578.2 UniProt: P20929-3
NEB ENST00000409198.5	TSL:5	c.194_195delCGinsTT p.Pro65Leu	missense	N/A	Prot: ENSP00000386259.1 UniProt: P20929-4

NEB ENST00000397345.8

TSL:5MANE Select

HGVSc / HGVSpc.194_195delCGinsTTp.Pro65Leu

Exon rankN/A

missense

Prot: ENSP00000380505.3UniProt: P20929-2

NEB ENST00000427231.7

TSL:5MANE Plus Clinical

HGVSc / HGVSpc.194_195delCGinsTTp.Pro65Leu

Exon rankN/A

missense

Prot: ENSP00000416578.2UniProt: P20929-3

NEB ENST00000409198.5

TSL:5

HGVSc / HGVSpc.194_195delCGinsTTp.Pro65Leu

Exon rankN/A

missense

Prot: ENSP00000386259.1UniProt: P20929-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	2.4

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence