2-151727790-CG-TA

Variant names:

• chr2-151727790-CG-TA
• NM_001164507.2:c.194_195delCGinsTA
• NEB p.Pro65Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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

The NM_001164508.2(NEB):c.194_195delCGinsTA (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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.39
• 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: 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

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.

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NEB NM_001164507.2	MANE Plus Clinical	c.194_195delCGinsTA p.Pro65Leu	missense	N/A	Prot: NP_001157979.2 UniProt:
	NEB NM_001164508.2	MANE Select	c.194_195delCGinsTA p.Pro65Leu	missense	N/A	Prot: NP_001157980.2 UniProt:
	NEB NM_001271208.2		c.194_195delCGinsTA p.Pro65Leu	missense	N/A	Prot: NP_001258137.2

NEB NM_001164507.2

MANE Plus Clinical

HGVSc / HGVSpc.194_195delCGinsTAp.Pro65Leu

Exon rankN/A

missense

Prot: NP_001157979.2UniProt: P20929-3

NEB NM_001164508.2

MANE Select

HGVSc / HGVSpc.194_195delCGinsTAp.Pro65Leu

Exon rankN/A

missense

Prot: NP_001157980.2UniProt: P20929-2

NEB NM_001271208.2

HGVSc / HGVSpc.194_195delCGinsTAp.Pro65Leu

Exon rankN/A

missense

Prot: NP_001258137.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NEB ENST00000397345.8	TSL:5MANE Select	c.194_195delCGinsTA p.Pro65Leu	missense	N/A	Prot: ENSP00000380505.3 UniProt:
	NEB ENST00000427231.7	TSL:5MANE Plus Clinical	c.194_195delCGinsTA p.Pro65Leu	missense	N/A	Prot: ENSP00000416578.2 UniProt:
	NEB ENST00000409198.5	TSL:5	c.194_195delCGinsTA p.Pro65Leu	missense	N/A	Prot: ENSP00000386259.1 UniProt:

NEB ENST00000397345.8

TSL:5MANE Select

HGVSc / HGVSpc.194_195delCGinsTAp.Pro65Leu

Exon rankN/A

missense

Prot: ENSP00000380505.3UniProt: P20929-2

NEB ENST00000427231.7

TSL:5MANE Plus Clinical

HGVSc / HGVSpc.194_195delCGinsTAp.Pro65Leu

Exon rankN/A

missense

Prot: ENSP00000416578.2UniProt: P20929-3

NEB ENST00000409198.5

TSL:5

HGVSc / HGVSpc.194_195delCGinsTAp.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

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

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.

Other links and lift over

hg19: chr2-152584304;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar